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Accuracy of a particular genetics test

Accuracy of a particular genetics test


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I am a newbie in biology and I am simply trying to discover the field of genomics.

Consider the question - Are genetic tests accurate?

I don't believe they are as the genes may not provide the complete information or maybe there are other genes responsible for a particular trait but they may not be known at the point when the test is conducted. This may not be the right answer though - I simply wish to understand from people here as to what they can say about the accuracy of these tests. If they are not accurate, can you explain why that is the case?


Like the comment said this question is very broad but Im going to try and clear some things up for you. A "genetic test" is just simply a test that tells you whether or not you have a certain genotype. Yes, it is often times used to tell if a person has a disease or not, but that doesnt always have to be the case. I may just want to know, for example, if a mouse I have carriers a certain transgene. The reason why genetic tests are good at determining if someone has a disease is because many diseases are simple, or at least have a well-defined genotype. Sure, you can make a genetic test for a complex disease like obesity if you want, but no one does this because as you pointed out in your question there are sometimes more than one gene involved, so a genetic test for that would not be very good.

But for genetic tests of diseases of a known genotype, they are very accurate. Of course you have some false positives and false negatives. Look up the terms selectivity and sensitivity. If you have a sensitive test you will catch a lot of people with the disease but also many false positives. If you have a selective test you will not have many false positives but you may miss people who actually have the disease. Its a trade-off. Testing someone twice will clear things up usually.

And then there are cases where you have a disease with a known genotype but still have an inaccurate genetic test on rare occasions. Heres a paper about a disease known as Spinal Muscular Atrophy. There is a genetic test that works 95% of the time but sometimes it does not match up with the phenotype. In the paper they find a mutation that explains why the genetic test does not match the phenotype. Two things are interesting about the paper. One, the genetic test is not wrong, its just that the phenotype is not what you'd expect. And two, not all people who have a discordant genetic test have this mutation. So whats going on in these patients and why their test doesnt match their phenotype is anyone's guess.

The first point is especially important so I will repeat it. The genetic test was not wrong, the phenotype just did not match it as expected. Genotype and phenotype are not always correlated, and mistakes can happen when you assume they are.


@von-mises summed it up nicely enough, but you'll want to read the Wikipedia articles on heredity and hereitability, in particular the latter. Our genes can tell us so much about ourselves, but it's not always that simple. As you mention, there are lots of other factors that could and usually do come into play. Often times there isn't just one gene, but rather many genes playing a role (these are called polygenic traits). For example, see my answer to a question on hair color; there are dozens of simple changes that can affect the color of hair and eyes. These complex traits are really hard to tease out!

Additionally, not everything is 100% from genes; the environment can also play a huge role. Often we talk about how heritable a gene or a trait is by giving a percent, meaning how much of is due to genes you inherit from your parents. The heritability of IQ is an interesting read for an introduction to the concept.

So, what is the use of the genetic tests? Well, for starters, ancestry is really interesting and useful for people. Not just paternity or maternity (which is obviously accurate and widespread) but knowing where you are from. 23andMe is a great service (I'm 2.9% Neanderthal!) for finding out where you came from genetically.

There are, additionally, a number of traits that we've studied, or that do have strong genetic factors. Sickle-cell disease is a classic example of something just from your genotype, whereas other things are less determinate; for example, the heritability of baldness is around 81%, and I know from my genome that I have a slightly lower chance of becoming bald. There are other, more serious health risks that people would want to be tested for (BRCA for breast cancer, LRRK2 for Parkinson's, APOE for Alzheimer's) as well as inherited traits that are very genetically determined (like sickle-cell or Tay-Sachs).

In short, the genetic tests are very good at determining what the genotype is, which can be very useful for certain traits but completely useless for others. The more we learn about what our genes do the more we learn how complicated the whole system is. We are more than just our genes.


How can consumers be sure a genetic test is valid and useful?

Before undergoing genetic testing, it is important to be sure that the test is valid and useful. A genetic test is valid if it provides an accurate result. Two main measures of accuracy apply to genetic tests: analytical validity and clinical validity. Another measure of the quality of a genetic test is its usefulness, or clinical utility.

Analytical validity refers to how well the test predicts the presence or absence of a particular gene or genetic change. In other words, can the test accurately detect whether a specific genetic variant is present or absent?

Clinical validity refers to how well the genetic variant being analyzed is related to the presence, absence, or risk of a specific disease.

Clinical utility refers to whether the test can provide information about diagnosis, treatment, management, or prevention of a disease that will be helpful to a consumer.

All laboratories that perform health-related testing, including genetic testing, are subject to federal regulatory standards called the Clinical Laboratory Improvement Amendments (CLIA) or even stricter state requirements. CLIA standards cover how tests are performed, the qualifications of laboratory personnel, and quality control and testing procedures for each laboratory. By controlling the quality of laboratory practices, CLIA standards are designed to ensure the analytical validity of genetic tests.

CLIA standards do not address the clinical validity or clinical utility of genetic tests. The Food and Drug Administration (FDA) requires information about clinical validity for some genetic tests. Additionally, the state of New York requires information on clinical validity for all laboratory tests performed for people living in that state. Consumers, health providers, and health insurance companies are often the ones who determine the clinical utility of a genetic test.

It can be difficult to determine the quality of a genetic test sold directly to the public. Some providers of direct-to-consumer genetic tests are not CLIA-certified, so it can be difficult to tell whether their tests are valid. If providers of direct-to-consumer genetic tests offer easy-to-understand information about the scientific basis of their tests, it can help consumers make more informed decisions. It may also be helpful to discuss any concerns with a health professional before ordering a direct-to-consumer genetic test.


Accuracy of a particular genetics test - Biology

School B iology Notes: The HUMAN GENOME - what is it? what is its importance?

Introduction to the GENOME of an organism & gene expression

The importance of knowing the human genome - the 'project'

Considering chromosomes, alleles, genotypes, phenotypes, variations

Doc Brown's school biology revision notes: GCSE biology, IGCSE biology, O level biology,

US grades 8, 9 and 10 school science courses or equivalent for

14-16 year old students of biology

This page will help you answer questions such as . What is a gene? What is a chromosome? What is the human genome? What are alleles? What is the difference between genotype and phenotype? Give examples of medical applications of data from the human genome project. Why is genetic testing controversial?

(a) The connection between DNA, genes, alleles, chromosomes and the genome

The genome is the whole of the genetic material of an organism - all of the DNA - coding and non-coding!

In animal and plant cells the genetic material (DNA) is contained in the cell nucleus and arranged in 'packages' called chromosomes.

Chromosomes often occur in pairs e.g. human cells have 23 pairs of chromosomes, 46 chromosomes in all.

Every chromosome is a very long strand of DNA that is coiled up to give it a characteristic shape.

Reminders: DNA is a very long natural polymer in which the monomer is a nucleotide that makes up the repeating unit in the molecular chain. The DNA molecule consists of two strands wound and bound together to form the double helix molecule.

For more on structure of DNA see DNA and Protein Synthesis gcse biology revision notes

A gene is a relatively short strand of DNA that forms a section of a chromosome that codes for a specific protein.

Each gene has the coded instructions to tell a cell to combine a particular sequence of amino acids to form a specific protein. In this case the monomer unit is an amino acid and the resulting polymer is called a protein.

Proteins control the development of an organism's characteristics and all its functions.

As if this wasn't complicated enough, there is an extra layer of complexity due to the existence of alleles!

Genes can exist in different versions called alleles - subtle differences in the genetic DNA code.

Each allele produces a different form of the same characteristic of an organism.

e.g. brown or blue eyes is a good example.

Each chromosome in a pair carries the same genes, BUT, they may carry different alleles.

The diagram below sums up the relationship between all the terms described and explained above.

Note: Genetic variants

Genetic variants (mutations) are caused by alterations in the common nucleotide sequences in the DNA of genes.

The term variant can be used to describe an alteration that may be benign (harmless), pathogenic (harmful), or of unknown significance.

The term variant is increasingly being used in place of the term mutation.

Variants are key to successful evolution because genotype changes (usually of the smaller type) can lead to changes in phenotype.

Human genetic variation is the genetic differences both within and among populations. There may be multiple variants of any given gene in the human population.

A mutation may defined as any change in a DNA compared to normal that results in a rare and abnormal variant .

For more on structure of DNA see DNA and Protein Synthesis gcse biology revision notes

For much more on mutations and variants see Genetic variation and mutations

(b) Genetic instructions and the characteristics of an organism

The combination of all alleles for each gene of an organism are called genotypes.

It is the genotypes of each organism that makes it unique.

However, the characteristics shown by an organism are called their phenotypes.

The phenotype of an organism is primarily determined by the genotype, but the phenotype can be influenced by the environment the organism is interacting with.

e.g. under what conditions does an organism grow and develop?

The diet of an animal can affect how well it grows and how healthy it is. A well nourished child grows strong and healthy. A malnourished child short of protein, vitamins etc. may have stunted growth, be too thin, physically weak and the immune system weakened so the individual is more susceptible to infectious diseases.

A flower exposed to lots of sunlight, rich soil and adequate water may grow a healthily rich green and have attractively coloured flowers. If a plant is deprived of enough sunlight, nutrients or water, it grows somewhat thinly and becomes limp, it tends to be yellowish rather than green and petal colours may fade.

In both of the above cases, the genotype determines the maximum healthy growth of organism, but this may be reduced by environmental factors.

Therefore the variation of the phenotype is determined by a combination of the genotype (genetic factors) and the conditions of growth and development (environmental factors).

(c) The importance of genome knowledge - the human genome project

The genome is the term that describes the total genetic material of an organism - all the DNA.

The human genome projects has mapped and identified all the genes found in human DNA.

Every organism has its own unique genome and scientists can now completely work it out - clever stuff!

Genome data is used to characterise species and help research plant and animal evolution patterns.

See note 3. below on the human genome.

The human genome has around 3 billion base pairs in the DNA sequences of the genes-chromosomes!

Apparently quite a lot of your DNA is 'junk', but don't worry, and we won't go into that, just study hard, play hard and enjoy life!

Thousands of scientists around the world have collaborated on the human genome project.

We now know the complete human genome and over 20,000 to 25,000 genes have been located on it, but although we know what many do (code for), there is much more to find out.

Around 1800 genes have been identified that relate to human diseases - and this data is the target of medical research to benefit medicine.

PLEASE NOTE that all humans share 99.9% of their genomes, which makes you think!

How is our understanding of the human genome helping science e.g. evolution theory or medicine?

Any new drug must be targeted at some specific medical condition where there is a need.

The target might be blocking the action of an enzyme or a gene with a chemical agent (drug) you can interfere with the development of a disease e.g. the anti-cancer drugs used in chemotherapy treatments to reduce the growth of tumour cells or kill them.

Studies of the genomes and resulting proteins in both plants and animals are proving useful to identify 'targets'.

You then have to find a chemical that will have an effect on the target, fortunately there are databases of chemicals that have been previously screened for likely effectiveness.

The screening might not initially indicate the best molecule to 'hit the target' in a biochemical sense, but, it may provide a starter molecule - which you can then modify to make different derivative molecules, one of which might provide a more effective treatment.

e.g. prediction and prevention of disease, testing for and treating inherited diseases, more effective medicines, BUT, there are ethical issues to deal with too.

1. It has been possible for genetic scientists to identify particular genes (genetic variants) in the genome that are linked to certain types of non-inherited diseases .

Hopefully it will lead to predicting predisposition to certain diseases, leading to early intervention with medical treatment and perhaps a preventing disease actually developing.

If you know what genes predispose people to certain diseases, medical advice can be more accurately given e.g. choice of diet and other lifestyle factors based on the results of genetic screening tests.

Many common diseases like cancer and heart conditions are caused by the interaction of different genes, as well as lifestyle factors.

See also I ntroduction to genetic variation - formation and consequence of mutations

and Stem cells and uses - leukaemia treatment

2. From the human genome project, by knowing the genes associated with an inherited disease ( genetic disorder ), we can understand it more clearly and then develop more effective treatments - which may involve genetic engineering itself.

We know inheriting certain genes greatly increase your risk of developing certain cancers, this can help with making lifestyle choices to minimise the risk of suffering from the disease - as with 1. above, its a sort of risk management situation.

In the UK newborn babies are routinely tested for particular genetic variants known to cause genetic disorders e.g. the double recessive allele that causes cystic fibrosis.

The results from genetic screening enables the medical treatment-management to begin promptly while the baby is still very young.

Children with leukaemia can have a genetic test to help decide which is the most effective treatment in terms of medication and its dose.

See further notes on genetic screening of an embryos or fetus (much more controversial)

and Introduction to the inheritance of characteristics and inherited disorders

It is hoped that all this new genetic science will lead to the development of better, and more personal, treatments for a wide range of medical conditions.

We are now developing drugs and other techniques that work at the molecular level in combating disease and tailored to suit the individual's body chemistry.

The variations in patients genetic variants (alleles) mean that one drug isn't necessarily as effective with all patients suffering from the same condition - so new drugs can be designed to suit these 'varying' patient situations.

3. We know certain alleles affect how our body responds to certain diseases and their treatment.

Scientists hope to use this knowledge to develop more effective drugs that can be specifically suited to patients with certain alleles in their genome.

Different drugs can be tested, and their effectiveness compared with the patient's alleles, and you can compare existing drugs with new ones.

It has been found that some breast cancer drugs are only effective in women if they have certain alleles in their genome.

4. To help in these medical quests, scientists are analysing the genomes of human pathogens to help us understand and control certain infectious diseases.

The complete genome of bacteria such as the deadly MRSA, which is resistant to antibiotics.

It is hoped that pathogen genome knowledge will allow swifter decisions as to the best treatment administered to patients i.e. determined by the genomics of the specific bacterial strain.

The science of human e volution and migration

The human genome project can be tackled by various genetic strategies.

(i) Analysis of data from people's Y chromosome inherited down the male line.

(ii) Analysing mitochondrial DNA inherited through mothers.

Our knowledge of the human genome is being used to trace the migration of certain populations across the continents of the world.

The latest research suggests that all modern humans have descended from a common ancestor who lived in Africa, and their descendents have spread over all over the Earth - moving by both land and sea.

This is known as the 'Out of Africa' theory and seems to have begun around 60 000 years ago.

Why did this happen?

Maybe change in climate, so seeking more food for hunter-gathering tribes?

It is known the climate in Africa at this time became much dryer - less rain, less plant life, less food for animals, less plants and animals for humans to eat.

All humans have a very similar genome .

In terms of ancestors - genetically, who you were and where you have been is 'hidden' in your genome! until, that is, modern DNA analysis reveals all .

However, as different populations of people migrated to different areas of the planet, small differences in DNA 'evolved' (incorporated) into their genome e.g. producing different skin or hair colour or facial features.

The genetic variation is as little as 0.001%, but even so, genetic scientists can work out when these new populations split off in a different 'genetic' and geographical direction.

People who are related will have an even more similar genome.

The human genome is being compared to some of closest relative in the world e.g. primates.

Ever since researchers sequenced the chimp genome in 2005, they have known that humans share about 99% of our DNA with chimpanzees, making them our closest living relatives - that should make you think!

(d) Genetic screening - using data from the human genome project - potential medical treatments - issues

Introduction

When you know that a particular allele causes an inherited genetic disorder you can take action e.g.

if an allele that causes an inherited disorder is identified, we could have regular medical checks for these specific diseases and get early diagnosis and subsequent treatment.

Genetic treatment might be able to cure the disease.

From the human genome project scientists can identify the genes and alleles that may be responsible for causing inherited disorders, and much faster prior to the mapping of the complete human genome.

Common diseases like cancer and heart conditions are caused by the interaction of our genes and our lifestyle factors.

If we know which genes predispose an individual to certain types of disease we could be given personal advice on diet and lifestyle (in general) to minimise the risk of suffering from particular diseases.

However, there are many issues to with genetic testing results e.g.

(i) From the point of view of potential parents, there maybe crucial choices regarding whether children may be born with a genetically inherited disorder - especially if both parents carried the same faulty allele.

(ii) Would insurance companies be allowed to see your 'genetic profile', are they entitled to know it e.g. as regards health or life insurance?

More on these points below in section (d)

Examples of using genetic testing

Example 1. A couple wishing to start a family might wish to know whether there is a risk of the baby developing a genetic disorder. This another aspect of family planning at the discretion of parents.

This can involve genetic testing at various point e.g.

1. Prior to conception, parents can be tested to see if they are carriers of a defective gene known to cause a genetic disorder.

It may be known that one of the parents comes from a family line where a genetic disorder has occurred.

The parents may not suffer from the genetic disorder, but they may be a carrier of the defective gene.

The genetic tests would show if any parent was a carrier and the probability of the baby inheriting the disorder - the parents can then make an 'informed decision' as to whether to have a child.

see Introduction to the inheritance of characteristics and inherited disorders

2. After conception or laboratory fertilisation, the embryo or fetus (embryo >8 weeks old) can be tested - see section (ii) below on embryonic genetic testing.

A pregnant woman can be tested by extracting a sample of DNA from the amniotic fluid which surrounds the fetus in the womb - there is a very small risk of causing a miscarriage.

The tests will show whether the foetus's DNA is carrying any of the genetic variants linked with a disorder.

If a positive test for such a variant is found, the couple can then make an 'informed decision' as to whether to terminate or continue with the pregnancy - a very personal and agonising family planning decision.

3. The newborn baby can be genetically tested to show whether a genetic disorder has been inherited allowing early intervention of medical treatment and subsequent long-term management of the disorder.

Example 2. Using in vitro fertilisation (IVF) embryos are fertilised in a laboratory and then implanted into the mother's womb.

Prior to implantation it is possible to remove a cell from an embryo and analyse the DNA i.e, the genes and likely genotypes/phenotypes.

This allows the detection of genetic disorders e.g. cystic fibrosis (described above) which is caused by the presence of one or more faulty genes.

You can choose to allow a genetic disorder free embryo to fully develop into a baby in the mother's womb - this minimises the baby inheriting the genetic variants linked with the disorder.

However, this ability to analyse genes in this way leads to ethical, social and economic concerns and questions about embryonic testing i.e. embryo screening for abnormal-undesired genetic traits, on which crucial decisions can be made e.g. termination of pregnancy.

e.g. after screening, embryos produced by IVF, containing abnormal alleles can be destroyed.

Example 3. Other points on genetic testing

Genome research data shows scientists the common genetic variations between people, most of which are benign and no danger to our health.

However, as I've already pointed out:

Some genetic variations are linked to our predisposition to certain disease - so this will help to design new drugs specifically tailored to suit people of a particular genetic trait.

In the UK newborn babies are routinely tested for particular genetic variants known to cause genetic disorders e.g. the double recessive allele that causes cystic fibrosis.

The results from genetic screening enables the medical treatment-management to begin promptly while the baby is still very young.

Arguments for embryonic/fetal screening and other genetic testing

(i) It stops newborn babies suffering as they grow up into adults.

(ii) Reducing the number of people suffering with a genetic disorder that is costly for healthcare systems to deal with.

(iii) Procedures like IVF, accompanied by genetic testing, are strictly regulated and parents are not allowed to choose desirable traits.

Parents are not allowed to choose the sex of their child, unless it is for good medical health reasons.

(iv) Other 'positive' points on genetic testing:

Early intervention for potentially serious diseases has already been mentioned.

Drugs for chemotherapy in cancer treatment are continually being developed and tested - you match a drugs performance against a person's specific genetic profile - this increases a 'working' database of treatment for future patients - another positive outcome from such treatment research is the minimising of side-effects which can quite drastic from ant-cancer drugs.

Arguments against embryonic/fetal screening and other genetic testing

Many objections centre around the ethical issues of IVF .

(i) IVF procedures often result in unused embryos being destroyed and some people consider this unethical - immoral, because you have destroyed a potential human life.

Even using embryos in research projects is considered to be unethical.

(ii) Terminations of IVF pregnancies on the grounds the baby may be born with a genetic disorder implies that the resulting children are undesirable and prejudice increased towards them.

Would potential parents feel under pressure NOT to have children with a potentially inherited genetic disorder.

(iii) The genetics and genetic testing of embryos before implantation in the mother's womb raises the ethical issue of preferential choice of characteristics of the baby e.g. choice of gender, eye colour irrespective of whether you allow a child to be born with disabilities.

(iv) Genetic screening is expensive and the costs of gene technology treatments are high.

The cost increases, the more personal the treatment, because the more specialised the drugs must be.

Surely this risks unfair access to these expensive treatments?

In the UK NHS treatment is free - BUT, is it locally available? Can you jump the queue by using private medicine?

In other countries, or UK private medicine - what does your insurance premium cover?

(v) The accuracy of genetic testing

Unfortunately, due to the complexity of DNA structure, genetic testing is not 100% accurate.

A positive test for a faulty gene, that is incorrect, will causing stress to the couple, and possibly the wrong decision to terminate a pregnancy because of fear of the baby inheriting a genetic disorder when there is actually no need to be concerned.

A negative test for a faulty gene, that is incorrect, means the couple are completely unprepared for the birth of a child with a genetically inherited disorder, causing considerable stress in their lives when the baby is born.

(vi) Other 'negative' points on genetic testing:

Is the use of gene technology good in the long term, since we don't actually know what the effects will be on future generations?

What might you think if you know from an early age you are more susceptible (more predisposed) to a particular disease? Won't this lead to stress thinking about it, especially if there isn't cure for it? Might you feel uneasy and worried if you 'seem' to exhibit symptoms?

Would you be discriminated against by insurance companies (e.g. insurance refusal or increased premiums) or employers (e.g. refused long-term job contract) if they knew you were likely to suffer from a genetically inherited disorder.

Society must decide on a code of conduct relating to potential discrimination AND privacy of your medical details.

Just imagine the problems caused if you genetic profile had to be submitted with a job application!

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Study Finds Inaccuracies in 40 Percent of DTC Genetic Testing Results

Shawna Williams
Mar 28, 2018

ISTOCK, STEVANOVICIGOR A small study of direct-to-consumer (DTC) genetic tests, conducted by clinical diagnostics company Ambry Genetics, found that 40 percent of the variants identified were false positives. The authors of the study, which appears today (March 28) in Genetics in Medicine, also note that among the variants that had been flagged as bringing increased risk of disease&mdasheither by the DTC testing companies or third-party interpretation services&mdasheight were in fact benign.

&ldquoSuch a high rate of a false positives in this particular study was unexpected,&rdquo says study coauthor Stephany Tandy-Connor of Ambry Genetics, in a statement. She notes that differences in testing methods may explain some of the differences between Ambry&rsquos results and those of the DTC testing companies.

Companies such as 23andMe and ancestry.com offer consumers what are sometimes known as recreational tests, typically through the mail, with no need to go through a doctor or genetic.

The research team analyzed the results of 49 patients whose records indicated they sought confirmatory testing through a medical provider after receiving worrying results. Of the 40 percent of gene variant testing results that Ambry did not confirm, almost all (16/17) were linked to cancer susceptibility, and one was for a connective tissue disorder.

“No test is accurate every time you run it,” genetic counselor and president of the National Society for Genetic Counselors Erica Ramos tells Lifehacker. Ramos works for Illumina, which partially owns DTC testing service Helix.

“Genetic testing needs to be interpreted by a qualified health-care professional in the context of several other factors, such as personal and family medical history,” the authors of the study conclude. “It is our hope that confirmatory testing and appropriate clinical management by all health-care professionals accompany DTC genetic testing for at-risk patients.”


How Accurate Are Online DNA Tests?

The age of consumer genomics has arrived. Nowadays you can send a vial of your spit in the mail and pay to see how your unique genetic code relates to all manner of human activity&mdashfrom sports to certain diets to skin cream to a preference for fine wines, even to dating.The most widespread and popular companies in this market analyze ancestry, and the biggest of these are 23andMe and AncestryDNA, both with more than five million users in their databases. These numbers dwarf the numbers of human genomes in scientific databases. Genetic genealogy is big business, and has gone mainstream. But how accurate are these tests&mdashtruly?

First, a bit of genetics 101. DNA is the code in your cells. It is the richest but also most complex treasure trove of information that we&rsquove ever attempted to understand. Three billion individual letters of DNA, roughly, organized into 23 pairs of chromosomes&mdashalthough one of those pairs is not a pair half the time (men are XY, women are XX). The DNA is arranged in around 20,000 genes (even though debate remains about what the definition of a gene actually is). And rather than genes, almost all of your DNA&mdash97 percent&mdashis a smorgasbord of control regions, scaffolding and huge chunks of repeated sections. Some of it is just garbage, left over from billions of years of evolution.

Modern genetics has unveiled a picture of immense complexity, one that we don&rsquot fully understand&mdashalthough we are certainly a long way from Mendel and his pea experiments, which first identified the units of inheritance we know as genes. Throughout the course of the 20th century we gained a firm grasp of the basics of biological inheritance: how genes are passed from one generation to another and how they encode the proteins that all life is built of, or by. In the 1980s we identified genes that had mutated, making faulty proteins, which could cause terrible diseases such as cystic fibrosis or muscular dystrophy, for example.

By 2003, the Human Genome Project had delivered the human DNA sequence in its entirety. One of the most important by-products of that endeavor was the advent of technology that allowed us to read DNA at unprecedented speed and for ever-decreasing costs. We can now pump out the genomes of hundreds of thousands of people for peanuts, and with that data comes greater and greater perspicacity into the profound questions of inheritance, evolution and disease. There&rsquos effectively infinite variation in human genomes, and scrutinizing our DNA helps us to understand what makes us human as a species and as individuals.

With the plummeting costs of gene sequencing came commercial interests. All of a sudden any company could set up shop, and in exchange for some cash and a vial of saliva, could extract your DNA from the cells in your mouth and sequence your genome. Alongside the behemoths 23andMe and AncestryDNA, dozens of companies have done just that.

There are two potential issues arising from the question of their results&rsquo accuracy. The first is somewhat trivial: Has the sequencing been done well? In critiquing this business, it seems fair to assume the data generated is accurate. But there have been some bizarre cases of failure, such as the company that failed to identify the sample DNA as coming not from a human, but from a dog. One recent analysis found 40 percent of variants associated with specific diseases from &ldquodirect to consumer&rdquo (DTC) genetic tests were shown to be false positives when the raw data was reanalyzed.

Assuming the tests are done accurately, some discrepancies can still arise from differences in the companies&rsquo DNA databases. Almost every DTC genetic test does not sequence your entire genome, but instead looks at positions in your DNA that are known to be of interest. When I was tested by 23andMe, they proclaimed I do not carry a version of a gene that is associated strongly with red hair. Another ancestry company said I did. This merely reflects the fact one company was looking at different variants of the gene that code for ginger hair.

If we assume the data generated is accurate, then the second question that arises is on the interpretation. And this is where it gets murky. Many of the positions of interest in your DNA are determined by experiments known as Genome Wide Association Studies, or GWAS (pronounced gee-woz). Take a bunch of people, as many as possible, that have a shared characteristic. This could be a disease, like cystic fibrosis (CF) or a normal trait, say, red hair. When you sequence all their genes, you look out for individual places in their DNA that are more similar within the test group than in another population. For CF, you would see a big spike in chromosome 7 because the majority of cases of CF are caused by a mutation in one gene. For redheads, you&rsquod see 16 or 17 spikes very close to one another, because there are multiple variants in the same gene that all bestow ginger locks. But for complex traits like taste or ones relating to diet or exercise, dozens of variants will emerge, and all of them only offer a probability of a predisposition toward a certain behavior as a result of your DNA, as measured in a population. This even applies to something as seemingly straightforward as eye color: A gene variant that is associated with blue eyes is still only a probability that you will have blue eyes, and it is perfectly possible to have two blue-eyed genes and not have blue eyes.

Genetics is a probabilistic science, and there are no genes &ldquofor&rdquo anything in particular. I have severe reservations about the utility of genetic tests that indicate one individual&rsquos propensity for certain conditions outside of a clinical setting if you don&rsquot have a PhD in genetics, these results can be misleading or even troubling. Even if, as I do, you carry a version of a gene which increases the probability of developing Alzheimer&rsquos disease, most people with this variant do not develop the disorder, which is also profoundly influenced by many lifestyle choices and some blind luck. There is little a geneticist can tell you with this information that will outweigh standard lifestyle advice: Don&rsquot smoke, eat a balanced diet, exercise regularly and wear sunscreen.

When it comes to ancestry, DNA is very good at determining close family relations such as siblings or parents, and dozens of stories are emerging that reunite or identify lost close family members (or indeed criminals). For deeper family roots, these tests do not really tell you where your ancestors came from. They say where DNA like yours can be found on Earth today. By inference, we are to assume that significant proportions of our deep family came from those places. But to say that you are 20 percent Irish, 4 percent Native American or 12 percent Scandinavian is fun, trivial and has very little scientific meaning. We all have thousands of ancestors, and our family trees become matted webs as we go back in time, which means that before long, our ancestors become everyone&rsquos ancestors. Humankind is fascinatingly closely related, and DNA will tell you little about your culture, history and identity.


Who Will Live To Be 100? Genetic Test Might Tell

If there were a medical test that could tell you whether you would live to 100, would you take it?

That's not the hypothetical question it once was. Scientists from Boston University are reporting they have a version of such a test.

Don't expect to see it on the market anytime soon. It's not 100 percent accurate -- and besides, what would you do with the information? But the researchers hope the tools they used to create the test will lead to a better understanding of the genetics of why some people live longer than others.

Searching For Longevity Genes

Geneticist Paola Sebastiani took DNA samples from participants in the New England Centenarian Study. All of the study participants lived to 100 or more.

Emma Hendrickson, who is more than 100 years old, is the oldest competitor in the history of the United States Bowling Congress Women's Championships. Hendrickson wasn't part of the centenarian study, but the scientists found genetic signatures — gene patterns that were present in subgroups of centenarians with particular characteristics — that may predict who will join her in the centenarians club. Liz Margerum/The Gazette-Journal via AP hide caption

Emma Hendrickson, who is more than 100 years old, is the oldest competitor in the history of the United States Bowling Congress Women's Championships. Hendrickson wasn't part of the centenarian study, but the scientists found genetic signatures — gene patterns that were present in subgroups of centenarians with particular characteristics — that may predict who will join her in the centenarians club.

Liz Margerum/The Gazette-Journal via AP

Sebastiani looked for differences between DNA from the centenarians and the DNA of normal-aged people. As she reports in the journal Science, she was able develop a computer model that used 150 genetic markers, specific bits of DNA scattered around the 23 pairs of human chromosomes, to predict who would be able to join the centenarian club.

"The accuracy of this model is 77 percent," she says.

The model also allowed Sebastiani to identify genetic signatures: gene patterns that were present in subgroups of centenarians with particular characteristics. For example, the subgroup that lived the longest was also the group most likely to have delayed onset of diseases that typically affect older people: dementia, cardiovascular disease, hypertension.

In other words, Sebastiani says not only did these people live long lives they lived long, healthy lives.

Test Is Not Ready For Prime Time

Sebastiani's co-author Thomas Perls says neither he nor Sebastiani has taken the test.

"Actually the various authors of the paper feel this isn't quite ready for prime time," says Perls.

Related Blog Post

Besides not being totally accurate, there's the question of what you would do with the information. He worries that people who found out they were unlikely to live to 100 might stop watching their weight or exercising.

Perls and Sebastiani agree that the real value of this study should be what it will tell scientists about the genetics of aging.

"At the moment this is a statistical analysis," says Sebastiani. "A lot of work still has to be done to then understand what is the biology, what is the contribution of all these genetic markers. So this is the first step."

More Experiments Are Needed

Geneticist Richard Myers of the Hudson Alpha Institute for Biotechnology in Huntsville, Ala., agrees. "It’s indicating experiments to do it's not telling how you would use this to affect human health," he says.

And Myers warns that sometimes models based on statistics can steer you in the wrong direction.

"This is sort of the first hint of regions of the genome that might be important for extreme longevity. You have a hint, and that's better than having nothing," he says.

But it does mean understanding the genetics of longevity will take a while, maybe even 100 years. If we live that long.


Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions

The material in this report originated in the Coordinating Center for Infectious Diseases, Mitchell L. Cohen, MD, Director National Center for Preparedness, Detection, and Control of Infectious Diseases, Rima Khabbaz, MD, Director and the Division of Laboratory Systems, Roberta B. Carey, PhD, Acting Director.

Corresponding preparer: Bin Chen, PhD, Division of Laboratory Systems, National Center for Preparedness, Detection, and Control of Infectious Diseases, Coordinating Center for Infectious Diseases, 1600 Clifton Road NE, MS G-23, Atlanta, GA 30329. Telephone: 404-498-2228 Fax: 404-498-2215 E-mail: [email protected]

Summary

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized as waived (from routine regulatory oversight) or nonwaived based on the complexity of the tests tests of moderate and high complexity are nonwaived tests. Laboratories that perform molecular genetic testing are subject to the general CLIA quality systems requirements for nonwaived testing and the CLIA personnel requirements for tests of high complexity. Although many laboratories that perform molecular genetic testing comply with applicable regulatory requirements and adhere to professional practice guidelines,specific guidelines for quality assurance are needed to ensure the quality of test performance. To enhance the oversight of genetic testing under the CLIA framework,CDC and the Centers for Medicare & Medicaid Services (CMS) have taken practical steps to address the quality management concerns in molecular genetic testing,including working with the Clinical Laboratory Improvement Advisory Committee (CLIAC). This report provides CLIAC recommendations for good laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions. The recommended practices address the total testing process (including the preanalytic,analytic,and postanalytic phases),laboratory responsibilities regarding authorized persons,confidentiality of patient information,personnel competency,considerations before introducing molecular genetic testing or offering new molecular genetic tests,and the quality management system approach to molecular genetic testing. These recommendations are intended for laboratories that perform molecular genetic testing for heritable diseases and conditions and for medical and public health professionals who evaluate laboratory practices and policies to improve the quality of molecular genetic laboratory services. This report also is intended to be a resource for users of laboratory services to aid in their use of molecular genetic tests and test results in health assessment and care. Improvements in the quality and use of genetic laboratory services should improve the quality of health care and health outcomes for patients and families of patients.

Introduction

Genetic testing encompasses a broad range of laboratory tests performed to analyze DNA, RNA, chromosomes, proteins, and certain metabolites using biochemical, cytogenetic, or molecular methods or a combination of these methods. In 1992, the regulations for the Clinical Laboratory Improvement Amendments of 1988 (CLIA) were published and began to be implemented. Since that time, advances in scientific research and technology have led to a substantial increase both in the health conditions for which genetic defects or variations can be detected with molecular methods and in the spectrum of the molecular testing methods (1). As the number of molecular genetic tests performed for patient testing has steadily increased, so has the number of laboratories that perform molecular genetic testing for heritable diseases and conditions (2,3). With increasing use in clinical and public health practices, molecular genetic testing affects persons and their families in every life stage by contributing to disease diagnosis, prediction of future disease risk, optimization of treatment, prevention of adverse drug response, and health assessment and management. For example, preconception testing for cystic fibrosis and other heritable diseases has become standard practice for the care of women who are either pregnant or considering pregnancy and are at risk for giving birth to an infant with one of these conditions (4). DNA-based diagnostic testing often is crucial for confirming presumptive results from newborn screening tests, which are performed for approximately 95% of the 4 million infants born in the United States each year (5,6). In addition, pharmacogenetic and pharmacogenomic tests, which identify individual variations in single-nucleotide polymorphisms, haplotype markers, or alterations in gene expression, are considered essential for personalized medicine, which involves customizing medical care on the basis of genetic information (7).

The expanding field of molecular genetic testing has prompted measures both in the United States and worldwide to assess factors that affect the quality of performance and delivery of testing services, the adequacy of oversight and quality assurance mechanisms, and the areas of laboratory practice in need of improvement. Problems that could affect patient testing outcomes that have been reported include inadequate establishment or verification of test performance specifications, inadequate personnel training or qualifications, inappropriate test selection and specimen submission, inadequate quality assurance practices, problems in proficiency testing, misunderstanding or misinterpretation of test results, and other concerns associated with one or more phases of the testing process (8--11).

Under CLIA, laboratory testing is categorized as waived testing or nonwaived (which includes tests of moderate and high complexity) based on the level of testing complexity. Laboratories that perform molecular genetic testing are subject to general CLIA requirements for nonwaived testing and CLIA personnel requirements for high-complexity testing no molecular genetic test has been categorized as waived or moderate complexity. Many laboratories also adhere to professional practice guidelines and voluntary or accreditation standards, such as those developed by the American College of Medical Genetics (ACMG), the Clinical and Laboratory Standards Institute (CLSI), and the College of American Pathologists (CAP), which provide specific guidance for molecular genetic testing (12--14). In addition, certain state programs, such as the New York State Clinical Laboratory Evaluation Program (CLEP), have specific requirements that apply to genetic testing laboratories in their purview (15). However, no specific requirements exist at the federal level for laboratory performance of molecular genetic testing for heritable diseases and conditions.

Since 1997, CDC and the Centers for Medicare & Medicaid Services (CMS) have worked with other federal agencies, professional organizations, standard-setting organizations, CLIAC, and other advisory committees to promote the quality of genetic testing and improve the appropriate use of genetic tests in health care. To enhance the oversight of genetic testing under CLIA, CMS developed a multifaceted action plan aimed at providing guidelines, including the good laboratory practice recommendations in this report, rather than prescriptive regulations (16). Many of the activities in the action plan have been implemented or are in progress, including 1) providing CMS and state CLIA surveyors with guidelines and technical training on assessing genetic testing laboratories for compliance with applicable CLIA requirements, 2) developing educational materials on CLIA compliance for genetic testing laboratories, 3) collecting data on laboratory performance in genetic testing, 4) working with CLIAC and standard-setting organizations on oversight concerns, and 5) collaborating with CDC and the Food and Drug Administration (FDA) on ongoing oversight activities (16). This plan also was supported by the Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) in its 2008 report providing recommendations regarding future oversight of genetic testing (1).

The purposes of this report are to 1) highlight areas of molecular genetic testing that have been recognized by CLIAC as needing specific guidelines for compliance with existing CLIA requirements or needing quality assurance measures in addition to CLIA requirements and 2) provide CLIAC recommendations for good laboratory practices to ensure the quality of molecular genetic testing for heritable diseases and conditions. These recommendations are intended primarily for genetic testing that is conducted to diagnose, prevent, or treat disease or for health assessment purposes. The recommendations are distinct from the good laboratory practice regulations for nonclinical laboratory studies under FDA oversight (21 CFR Part 58) (17).The recommended laboratory practices provide guidelines for ensuring the quality of the testing process (including the preanalytic, analytic, and postanalytic phases of molecular genetic testing), laboratory responsibilities regarding authorized persons, confidentiality of patient information, and personnel competency. The recommendations also address factors to consider before introducing molecular genetic testing or offering new molecular genetic tests and the quality management system approach in molecular genetic testing. Implementation of the recommendations in laboratories that perform molecular genetic testing for heritable diseases and conditions and an understanding of these recommendations by users of laboratory services are expected to prevent or reduce errors and problems related to test selection and requests, specimen submission, test performance, and reporting and interpretation of results, leading to improved use of molecular genetic laboratory services, better health outcome for patients, and in many instances, better health outcomes for families of patients. In future reports, recommendations will be provided for good laboratory practices focusing on other areas of genetic testing, such as biochemical genetic testing, molecular cytogenetic testing, and somatic genetic testing.

Background

With the completion of the human genome project, discoveries linking genetic mutations or variations to specific diseases and biologic processes are frequently reported (18). The rapid progress in biomedical research, accompanied by advances in laboratory technology, have led to increased opportunities for development and implementation of new molecular genetic tests. For example, the number of heritable diseases and conditions for which clinical genetic tests are available more than tripled in 8 years, from 423 diseases in November 2000 to approximately 1,300 diseases and conditions in October 2008 (2,19). Molecular genetic testing is performed not only to detect or confirm rare genetic diseases or heritable conditions (20) but also to detect mutations or genetic variations associated with more common and complex conditions such as cancer (21,22), coagulation disorders (23), cardiovascular diseases (24), and diabetes (25). As the rapid pace of genetic research results in a better understanding of the role of genetic variations in diseases and health conditions, the development and clinical use of molecular genetic tests continues to expand (26--28).

Despite considerable information gaps regarding the number of U.S. laboratories that perform molecular genetic tests for heritable diseases and conditions and the number of specific genetic tests being performed (1), molecular genetic testing is one of the areas of laboratory testing that is increasing most rapidly. Molecular genetic tests are performed by a broad range of laboratories, including laboratories that have CLIA certificates for chemistry, pathology, clinical cytogenetics, or other specialties or subspecialties (11). Although nationwide data are not available, data from state programs indicate considerable increases in the numbers of laboratories that perform molecular genetic tests. For example, the number of approved laboratories in the state of New York that perform molecular genetic testing for heritable diseases and conditions increased 36% in 6 years, from 25 laboratories in February 2002 to 34 laboratories in October 2008 (29).

Although comprehensive data on the annual number of molecular genetic tests performed nationwide are not available, industry reports indicate a steady increase in the number of common molecular genetic tests for heritable diseases and conditions, such as mutation testing for cystic fibrosis and factor V Leiden thrombophilia (3). The number of cystic fibrosis mutation tests has increased significantly since 2001, pursuant to the recommendations of the American College of Obstetricians and Gynecologists and ACMG for preconception and prenatal carrier screening (30,31). The DNA-based cystic fibrosis mutation tests are now considered to be some of the most commonly performed genetic tests in the United States and have become an essential component of several state newborn screening programs for confirming presumptive screening results of infants (32). The overall increase in molecular genetic testing from 2006 to 2007 worldwide has been reported to be 15% in some market analyses, outpacing other areas of molecular diagnostic testing (33).

CLIA Oversight for Molecular Genetic Testing

In 1988, Congress enacted Public Law 100-578, a revision of Section 353 of the Public Health Service Act (42 U.S.C. 263a) that amended the Clinical Laboratory Improvement Act of 1967 and required the Department of Health and Human Services (HHS) to establish regulations to ensure the quality and reliability of laboratory testing on human specimens for disease diagnosis, prevention, or treatment or for health assessment purposes. In 1992, HHS published CLIA regulations that describe requirements for all laboratories that perform patient testing (34). Facilities that perform testing for forensic purposes only and research laboratories that test human specimens but do not report patient-specific results are exempt from CLIA regulations (34). CMS (formerly the Health Care Financing Administration) administers the CLIA laboratory certification program in conjunction with FDA and CDC. FDA is responsible for test categorization, and CDC is responsible for CLIA studies, convening CLIAC, and providing scientific and technical support to CMS. CLIAC was chartered by HHS to provide recommendations and advice regarding CLIA regulations, the impact of CLIA regulations on medical and laboratory practices, and modifications needed to CLIA standards to accommodate technological advances.

In 2003, CMS and CDC published CLIA regulatory revisions to reorganize and revise CLIA requirements for quality systems for nonwaived testing and the laboratory director qualifications for high-complexity testing (35). The revised regulations included facility administration and quality system requirements for every phase of the testing process (35). Requirements for the clinical cytogenetics specialty also were reorganized and revised. Other genetic tests, such as molecular genetic tests, are not recognized as a specialty or subspecialty under CLIA. However, because these tests are considered high complexity, laboratories that perform molecular genetic testing for heritable diseases and conditions must meet applicable general CLIA requirements for nonwaived testing and the personnel requirements for high-complexity testing (36).

To enhance oversight of genetic testing under CLIA, CMS developed a plan to promote a comprehensive approach for effective application of current regulations and to provide training and guidelines to surveyors and laboratories that perform genetic testing (16). CDC and CMS also have been assessing the need to revise and update CLIA requirements for proficiency testing programs and laboratories, taking into consideration the need for improved performance evaluation for laboratories that perform genetic testing (37).

Concerns Related to Molecular Genetic Testing

Studies and reports since 1997 have revealed a broad range of concerns related to molecular genetic testing for heritable diseases and conditions, including safe and effective translation of research findings into patient testing, the quality of test performance and results interpretation, appropriate use of testing information and services in health management and patient care, the adequacy of quality assurance measures, and concerns involving the ethical, legal, economic, and social aspects of molecular genetic testing (1,9,22,38,39). Some of these concerns are indicative of the areas of laboratory practice that are in need of improvement, such as performance establishment and verification, proficiency testing, personnel qualifications and training, and results reporting (1,9,11,22,39).

Errors Associated with and Needed Improvements in the Three Phases of Molecular Genetic Testing

Studies have indicated that although error rates associated with different areas of laboratory testing vary (40), the overall distribution of errors reported in the preanalytic, analytic, and postanalytic phases of the testing process are similar for many testing areas, including molecular genetic testing (9,11,39,40). The preanalytic phase encompasses test selection and ordering and specimen collection, processing, handling, and delivery to the testing site. The analytic phase includes selection of test methods, performance of test procedures, monitoring and verification of the accuracy and reliability of test results, and documentation of test findings. The postanalytic phase includes reporting test results and archiving records, reports, and tested specimens (41).

Studies have indicated that errors are more likely to occur during the preanalytic and postanalytic phases of the testing process than during the analytic phase, with most errors reported for the preanalytic phase (40,42--44). In the preanalytic phase, inappropriate selection of laboratory tests has been a significant source of errors (42,43). Misuse of laboratory services, such as unnecessary or inappropriate test requests, might lead to increased risk for medical errors, adverse patient outcome, and increased health-care costs (43). Although no study has determined the overall number of molecular genetic tests performed that could be considered unwarranted or unnecessary, a study of the use and interpretation of adenomatous polyposis coli gene (APC) testing for familial adenomatous polyposis and other heritable conditions associated with colonic polyposis indicated that 17% of the cases evaluated did not have valid indications for testing (22).

Although data are limited, studies also indicate that improvements are needed in the analytic phase of molecular genetic testing. A study of the frequency and severity of errors associated with DNA-based genetic testing revealed that errors related to specimen handling in the laboratory and other analytic steps ranged from 0.06% to 0.12% of approximately 92,000 tests evaluated (39). A subsequent meta-analysis indicated that these self-reported error rates were comparable to those detected in nongenetic laboratory testing (40). An analysis of performance data from the CAP molecular genetic survey program during 1995--2000 estimated the overall error rate for cystic fibrosis mutation analysis to be 1.5%, of which approximately 50% of the errors occurred during the analytic or postanalytic phases of testing (45). Unrecognized sequence variations or polymorphisms also could affect the ability of molecular genetic tests to detect or distinguish the genotypes being analyzed, leading to false-positive or false-negative test results. Such problems have been reported for some commonly performed genetic tests such as cystic fibrosis mutation analysis and testing for HFE-associated hereditary hemochromatosis (46,47).

The postanalytic phase of molecular genetic testing involves analysis of test results, preparation of test reports, and results reporting. The study on the use of the APC gene testing and interpretation of test results indicated that lack of awareness among health-care providers of APC test limitations was a primary reason for misinterpretation of test results (22). In a study assessing the comprehensiveness and usefulness of reports for cystic fibrosis and factor V Leiden thrombophilia testing, physicians in many medical specialties considered reports that included information beyond that specified by the general CLIA test report requirements to be more informative and useful than test reports that only met CLIA requirements additional information included patient race/ethnicity, clinical history, reasons for test referral, test methodology, recommendations for follow-up testing, implications for family members, and suggestions for genetic counseling (48). Consistent with these findings, international guidelines for quality assurance in molecular genetic testing recommend that molecular genetic test reports be accurate, concise, and comprehensive and communicate all essential information to enable effective decision-making by patients and health care professionals (49).

Proficiency Testing

Proficiency testing is a well-established practice for monitoring and improving the quality of laboratory testing (50,51) and is a key component of the external quality assessment process. Studies have indicated that using proficiency testing samples that resemble actual patient specimens could improve monitoring of laboratory performance (50,52--54). Participation in proficiency testing has helped laboratories reduce analytic deficiencies, improve testing procedures, and take steps to prevent future errors (55--59).

CLIA regulations have not yet included proficiency testing requirements for molecular genetic tests. Laboratories that perform molecular genetic testing must meet the general CLIA requirement to verify, at least twice annually, the accuracy of the genetic tests they perform (§493.1236[c]) (36). Laboratories may participate in available proficiency testing programs for the genetic tests they perform to meet this CLIA alternative performance assessment requirement. Proficiency testing participation correlates significantly with the quality assurance measures in place among laboratories that perform molecular genetic testing (9,10). Because proficiency testing is a rigorous external assessment for laboratory performance, in 2008, SACGHS recommended that proficiency testing participation be required for all molecular genetic tests for which proficiency testing programs are available (1). Formal molecular genetic proficiency testing programs are available only for a limited number of tests for heritable diseases and conditions in addition, the samples provided often are purified DNA, which do not typically require performance of all steps of the testing process, such as nucleic acid extraction and preparation (60). For many genetic conditions that are either rare or for which testing is performed by one or a few laboratories, substantial challenges in developing formal proficiency testing programs have been recognized (1).

Development of effective alternative performance assessment approaches to proficiency testing is essential for ensuring the quality of molecular genetic testing (1). Professional guidelines have been developed for laboratories to evaluate and monitor test performance when proficiency testing programs are not available (61). However, reports of the CAP molecular pathology on-site inspections indicate that deficiencies related to participation in interlaboratory comparison or alternative performance assessment are among the most frequently identified deficiencies, accounting for 3.9% of all deficiencies cited (62).

Clinical Validity and Potential Risks Associated with Certain Molecular Genetic Tests

The ability of a test to diagnose or predict risk for a particular health condition is the test's clinical validity, which often is measured by clinical (or diagnostic) sensitivity, clinical (or diagnostic) specificity, and predictive values of the test for a given health condition. Clinical validity can be influenced by factors such as the prevalence of the disease or health condition, penetrance (proportion of persons with a mutation causing a particular disorder who exhibit clinical symptoms of the disorder), and modifiers (genetic or environmental factors that might affect the variability of signs or symptoms that occur with a phenotype of a genetic alteration). For genetic tests, clinical validity refers to the ability of a test to detect or predict the presence or absence of a particular disease or phenotype and often corresponds to associations between genotypes and phenotypes (1,28,63--69). The usefulness of a test in clinical practice, referred to as clinical utility, involves identifying the outcomes associated with specific test results (28). Clinical validity and clinical utility should be assessed individually for each genetic test because the implications might vary depending on the health condition and population being tested (38).

As advances in genomic research and technology result in rapid development of new genetic tests, concerns have been raised that certain tests, particularly predictive genetic tests, could become available without adequate assessment of their validity, benefits, and utility. Consequently, health professionals and consumers might not be able to make a fully informed decision about whether or how to use these tests. In 1997, a task force formed by a National Institutes of Health (NIH)--Department of Energy workgroup recommended that laboratories that perform patient testing establish clinical validity for the genetic tests they develop before offering them for patient testing and carefully review and document evidence of test validity if the test has been developed elsewhere (70). This recommendation was later included in a report of the Secretary's Advisory Committee on Genetic Testing (SACGT), which was established in 1998 to advise HHS on medical, scientific, ethical, legal, and social concerns raised by the development and use of genetic tests (38).

Public concerns about inadequate knowledge or documentation of the clinical validity of certain genetic tests were also recognized by SACGHS, the advisory committee that was established by HHS in 2002 to supersede SACGT (1). SACGHS recommended the development and support of sustainable public-private collaborations to fill the gaps in knowledge of the analytic validity, clinical validity, clinical utility, economic value, and population health impact of molecular genetic tests (1). Collaborative efforts that have been recognized include the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) program, a CDC initiative to establish and evaluate a systematic, evidence-based process for assessing genetic tests and other applications of genomic technology in transition from research to clinical practice and public health (71), and the Collaboration, Education, and Test Translation (CETT) Program, which is overseen by the NIH Office of Rare Diseases to promote the effective transition of potential genetic tests for rare diseases from research settings into clinical settings (72).

The increase in direct-to-consumer (DTC) genetic testing (i.e., genetic tests offered directly to consumers with no health-care provider involvement) has raised concerns about the potential risks or misuses of certain genetic tests (73). As of October 2008, consumers could directly order laboratory tests in 27 states in another 10 states, consumer-ordered tests are allowed under defined circumstances (74). As DTC genetic tests become increasingly available, various genetic profile tests have been marketed directly to the public that claim to answer questions regarding cardiovascular risks, drug metabolism, dietary arrangements, and lifestyles (73). In addition, DTC advertisements have caused a substantial increase in the demand for molecular genetic tests, such as those for hereditary breast and ovarian cancers (75,76). Although allowing easy access to the testing services, DTC genetic testing has raised concerns about the potential for inadequate pretest decision-making, misunderstanding of test results, access to tests of questionable clinical value, lack of necessary follow-up, and unexpected additional responsibilities for primary care physicians (77--80). Both the government and professional organizations have developed educational materials that provide guidance to consumers, laboratories, genetics professionals, and professional organizations regarding DTC genetic tests (80--82).

Personnel Qualifications and Training

Studies indicate that qualifications of laboratory personnel, including training and experience, are critical for ensuring quality performance of genetic testing, because human error has the greatest potential influence on the quality of laboratory test results (9,83,84). A study of laboratories in the United States that perform molecular genetic testing suggested that laboratory adherence to voluntary quality standards and guidelines for genetic testing was significantly associated with laboratories directed or supervised by persons with board certification in medical genetics (9). Results of an international survey revealed a similar correlation between the quality assurance practices of a molecular genetic testing laboratory and the formal training of the laboratory director (10). Overall, the concerns recognized in publications and documented cases support the need to have trained, qualified personnel at all levels to ensure the quality of all phases of the genetic testing process.

Methods

Information Collection and Assessment

To monitor and assess the scope and growth of molecular genetic testing in the United States, data were collected and analyzed from scientific articles, government reports, the CMS CLIA database, information from state programs, studies by professional groups, publicly available directories and databases of laboratories and laboratory testing, industry reports, and CDC studies (1--3,5,6,9,29,38,83,85--88). To evaluate factors in molecular genetic testing that might affect testing quality and to identify areas that would benefit from quality assurance guidelines, various documents were considered, including professional practice guidelines, CAP laboratory accreditation checklists, CLSI guidelines, state requirements, and international guidelines and standards (12--15,49,61,89--95).

Development of CLIAC Recommendations for Good Laboratory Practices in Molecular Genetic Testing

Since 1997, CLIAC has provided HHS with recommendations on approaches needed to ensure the quality of genetic testing (37). At the February 2007 CLIAC meeting, CLIAC asked CDC and CMS to clarify critical concerns in genetic testing oversight and to provide a status report at the subsequent CLIAC meeting. At the September 2007 CLIAC meeting, CDC presented an overview of the regulatory oversight and voluntary measures for quality assurance of genetic testing and described a plan to develop and publish educational material on good laboratory practices. CDC solicited CLIAC recommendations to address concerns that presented particular challenges related to genetic testing oversight, including establishment and verification of performance specifications, control procedures for molecular amplification assays, proficiency testing, genetic test reports, personnel competency assessment, and the definition of genetic tests. CLIAC recommended convening a workgroup of experts in genetic testing to consider these concerns and provide input for CLIAC deliberation.

The CLIAC Genetic Testing Good Laboratory Practices Workgroup was formed. The workgroup conducted a series of meetings on the scope of laboratory practice recommendations needed for genetic testing and suggested that recommendations first be developed for molecular genetic testing for heritable diseases and conditions. The workgroup evaluated good laboratory practices for all phases of the genetic testing process after reviewing professional guidelines, regulatory and voluntary standards, accreditation checklists, international standards and guidelines, and other documents that provided general or specific quality standards applicable to molecular genetic testing for heritable diseases and conditions (1,12--15,36,41,49,61,80,82,91--109). The workgroup also reviewed information on the HHS-approved and other certification boards for laboratory personnel and the number of persons certified in each of the specialties for which certification is available (110--118). Workgroup suggestions were reported to CLIAC at the September 2008 committee meeting. The CLIAC recommendations were formed on the basis of the workgroup report and additional CLIAC recommendations. The committee recommended that CDC include the CLIAC-recommended good laboratory practices for molecular genetic testing in the planned publication. Summaries of CLIAC meetings and CLIAC recommendations are available (37).

Recommended Good Laboratory Practices

The following recommended good laboratory practices are for areas of molecular genetic testing for heritable diseases and conditions in need of guidelines for complying with existing CLIA requirements or in need of additional quality assurance measures. These recommendations are not intended to encompass the entire realm of laboratory practice they are meant to provide guidelines for specific quality concerns in the performance and delivery of laboratory services for molecular genetic testing for heritable diseases and conditions.

These recommendations address laboratory practices for the total testing process, including the preanalytic, analytic, and postanalytic phases of molecular genetic testing. The recommendations for the preanalytic phase include guidelines for laboratory responsibilities for providing information to users of laboratory services, informed consent, test requests, specimen submission and handling, test referrals, and preanalytic systems assessment. The recommendations for the analytic phase include guidelines for establishment and verification of performance specifications, quality control procedures, proficiency testing, and alternative performance assessment. The recommendations for the postanalytic phase include guidelines for test reports, retention of records and reports, and specimen retention. The recommendations also address responsibilities of laboratories regarding authorized persons, confidentiality of patient information and test results, personnel competency, factors to consider before introducing molecular genetic testing or offering new molecular genetic tests, and the potential benefits of the quality management system approach in molecular genetic testing. Recommendations are provided in relation to applicable provisions in the CLIA regulations and, when necessary, are followed by a description of how the recommended practices can be used to improve quality assurance and quality assessment for molecular genetic testing. A list of terms and abbreviations used in this report also is provided (Appendix A).

The Preanalytic Testing Phase

Test Information to Provide to Users of Laboratory Services

Laboratories are responsible for providing information regarding the molecular genetic tests they perform to users of their services users include authorized persons under applicable state law, health-care professionals, patients, referring laboratories, and payers of laboratory services. Laboratories should review the genetic tests they perform and the procedures they use to provide and update the recommended test information that follows. At a minimum, laboratories should ensure that the test information is available from accessible sources such as websites, service directories, information pamphlets or brochures, newsletters, instructions for specimen submission, and test request forms. Laboratories that already provide the information from these sources should continue to do so. However, laboratories also might decide to provide the information more directly to their users (e.g., by telephone, e-mail, or in an in-person meeting) and should determine the situations in which such direct communication is necessary. The complexity of language used should be appropriate for the particular laboratory user groups (e.g., for patients, plain language understandable by the general public).

Test selection, test performance, and specimen submission. Laboratories should provide information regarding the molecular genetic tests they perform to users of their services to facilitate appropriate test selection and requests, specimen handling and submission, and patient care. Each laboratory that performs molecular genetic testing for heritable diseases and conditions should provide the following information to its users:

  • Information necessary for selecting appropriate tests, including a list of the molecular genetic tests the laboratory performs. For each molecular genetic test, the following information should be provided:

--- Intended use of the test, including the nucleic acid target of the test (e.g., genes, sequences, mutations, or polymorphisms), the purpose of testing (e.g., diagnostic, preconception, or predictive), and the recommended patient populations

--- Indications for testing

--- Test method to be used, presented in user-friendly language in relation to the performance specifications and the limitations of the test (with Current Procedural Terminology [CPT] codes included when appropriate)

--- Specifications of applicable performance characteristics, including information on analytic validity and clinical validity

--- Limitations of the test

--- Whether testing is performed with an FDA-approved or FDA-cleared test system, with a laboratory-developed test or test system that is not approved or cleared by FDA, or with an investigational test under FDA oversight

  • Information on appropriate collection, handling, transport, and submission of specimens
  • Patient information necessary for the laboratory to perform the test and report test results, including relevant clinical or laboratory information, and, if applicable, racial/ethnic information, family history, pedigree, and consent information in compliance with federal, state, and local requirements
  • A statement indicating that test results are likely to have implications for the family members of the patient
  • Availability of laboratory consultations regarding test selection and ordering, specimen submission, results interpretation, and implications of test results

Cost. When possible and practical, laboratories should provide users with information on the charges for molecular genetic tests being performed. Estimating the expenses that a patient might incur from a particular genetic test might be difficult for certain laboratories and providers because fee schedules of individual laboratories can vary depending on the health-care payment policy selections of each patient. However, advising the patient and family members of the financial implications of the tests, whenever possible, facilitates informed decision-making.

Discussion. Under CLIA, laboratories are required to develop and follow written policies and procedures for specimen submission and handling, specimen referral, and test requests (42 CFR §§493.1241 and 1242). Laboratories must ensure positive identification and optimum integrity of specimens from the time of collection or receipt through the completion of testing and reporting of test results (42 CFR §493.1232). In addition, laboratories that perform nonwaived testing must ensure that a qualified clinical consultant is available to assist laboratory clients with ordering tests appropriate for meeting clinical expectations (42 CFR §493.1457[b]). The recommended laboratory practices in this report describe laboratory responsibilities for ensuring appropriate test requests and specimen submission for the molecular genetic tests they perform, in addition to laboratory responsibilities for meeting CLIA requirements. The recommendations emphasize the role of laboratories in providing specific information needed by users before decisions are made regarding test selection and ordering, based on consideration of several factors.

First, molecular genetic tests for heritable diseases and conditions are being rapidly developed and increasingly used in health-care settings. Users of laboratory services need the ability to easily access information regarding the intended use, performance specifications, and limitations of the molecular genetic tests a laboratory offers to determine appropriate testing for specific patient conditions.

Second, many molecular genetic tests are performed using laboratory-developed tests or test systems. The performance specifications and limitations of the testing might vary among laboratories, even for the same disease or condition, depending on the specific procedures used. Users of laboratory services who are not provided information related to the appropriateness of the tests being considered might select tests that are not indicated or cannot meet clinical expectations.

Third, for many heritable diseases and conditions, test performance and interpretation of test results require information regarding patient race/ethnicity, family history, and other pertinent clinical and laboratory information. Informing users before tests are ordered of the specific patient information needed by the laboratory should facilitate test requests and allow prompt initiation of appropriate testing procedures and accurate interpretation of test results.

Finally, providing information to users on performance specifications and limitations of tests before test selection and ordering prepares users of laboratory services for understanding test results and implications. CLIA test report requirements (42 CFR §493.1291[e]) indicate that laboratories are required to provide users of their services, on request, with information on laboratory test methods and the performance specifications the laboratory has established or verified for the tests. However, for molecular genetic tests for heritable diseases and conditions, laboratories should provide test performance information to users before test selection and ordering, rather than waiting for a request after the test has been performed. The information provided in the preanalytic phase must be consistent with information included on test reports.

Providing molecular genetic testing information to users before tests are selected and ordered should improve test requests and specimen submission and might reduce unnecessary or unwarranted testing. The recommended practices also might increase informed decision-making, improve interpretation of results, and improve patient outcome.

Informed Consent

A person who provides informed consent voluntarily confirms a willingness to undergo a particular test, after having been informed of all aspects of the test that are relevant to the patient's decision (49). Informed consent for genetic testing or specific types of genetic tests is required by law in certain states as of June 2008, 12 states required that informed consent be obtained before a genetic test is requested or performed (119). In addition, certain states (e.g., Massachusetts, Michigan, Nebraska, New York, and South Dakota) have included required informed consent components in their statutes [97,120--123]) (Appendix B). These state statutes can be used as examples for laboratories in other states that are developing specific informed consent forms. Professional organizations recommend that informed consent be obtained for testing for many inherited genetic conditions (12,13). CLIA regulations have no requirements for laboratory documentation of informed consent for requested tests however, medical decisions for patient diagnosis or treatment should be based on informed decision-making (124). Regardless of whether informed consent is required, laboratories that perform molecular genetic tests for heritable diseases and conditions should be responsible for providing users with the information necessary to make informed decisions.

Informed consent is in the purview of the practice of medicine the persons authorized to order the tests are responsible for obtaining the appropriate level of informed consent (67). Unless mandated by state or local requirements, obtaining informed consent before performing a test generally is not considered a laboratory responsibility. For molecular genetic testing for heritable diseases and conditions, not all tests require written patient consent before testing (125). However, when informed consent for patient testing is recommended or required by law or other applicable requirements as a method for documenting the process and outcome of informed decision-making, laboratories should ensure that certain practices are followed:

  • Be available to assist users of laboratory services with determining the appropriate level of informed consent by providing useful and necessary information.
  • Include appropriate methods for documenting informed consent on test request forms, and determine whether the consent information is provided with the test request before initiating testing. Laboratories may determine situations in which a patient specimen can be stabilized until informed consent is obtained, following the practices for specimen retention recommended in these guidelines.

Laboratories should refer to professional guidelines for additional information regarding informed consent for molecular genetic tests and should consider available models when developing the content, format, and procedures for documentation of patient consent.

Test Requests

CLIA requirements (42 CFR §493.1241[c]) specify that laboratories that perform nonwaived testing must ensure that the test request solicits the following information: 1) the name and address or other suitable identifiers of the authorized person requesting the test and (if applicable) the person responsible for using the test results, or the name and address of the laboratory submitting the specimen, including (if applicable) a contact person to enable reporting of imminently life-threatening laboratory results or critical values 2) patient name or a unique patient identifier 3) sex and either age or date of birth of the patient 4) the tests to be performed 5) the source of the specimen (if applicable) 6) the date and (if applicable) time of specimen collection and 7) any additional information relevant and necessary for a specific test to ensure accurate and timely testing and reporting of results, including interpretation (if applicable). For molecular genetic testing for heritable diseases and conditions, laboratories must comply with these CLIA requirements and should solicit the following additional information on test requests:

  • Patient name and any other unique identifiers needed for testing
  • Patient date of birth
  • Indication for testing and relevant clinical or laboratory information
  • Patient racial/ethnic information (if applicable)
  • Information on patient family history, pedigree, or both that is pertinent to the disease or condition being evaluated or the testing to be performed (if applicable)
  • Appropriate international classification of diseases (ICD) codes or other information indicating diseases or conditions for which the patient is being tested (e.g., codes associated with an advance beneficiary notice)
  • If applicable, indication that the appropriate level of informed consent has been obtained in compliance with federal, state, and local requirements

Patient name and any other unique identifiers needed for testing. CLIA test request requirements indicate that laboratories must solicit patient names or unique patient identifiers on test requests (42 CFR §493.1241[c][2]). Laboratories that perform molecular genetic testing for heritable diseases and conditions should ensure that at least two unique identifiers are solicited on these test requests, which should include patient names, when possible, and any other unique identifiers needed to ensure patient identification. In certain situations (e.g., compatibility testing for which donor names are not always provided to the laboratory), an alternative unique identifier is appropriate.

Date of birth. CLIA requirements specify that test requests must solicit the sex and either age or date of birth of the patient (42 CFR §493.1241[c][3]). For molecular genetic testing for heritable diseases and conditions, patient date of birth is more informative than age and should be obtained when possible.

Indications for testing, relevant clinical and laboratory information, patient race/ethnicity, family history, and pedigree. Obtaining information on indications for testing, relevant clinical or laboratory information, patient racial/ethnic background, family history, and pedigree is critical for selecting appropriate test methods, determining the mutations or variants to be tested, interpreting test results, and timely reporting of test results. Genetic conditions often have different disease prevalences with various mutation frequencies and distributions among racial/ethnic groups. Unique, or private, mutations or genotypes might be present only in specific families or can be associated with founder effects (i.e., gene mutations observed in high frequency in a specific population because of the presence of the mutation in a single ancestor or small number of ancestors in the founding population). Family history and other relevant clinical or laboratory information are often important for determining whether the test requested might meet the clinical expectations, including the likelihood of identifying a disease-causing mutation. Specific race/ethnicity, family history, and other pertinent information to be solicited on a test request should be determined according to the specific disease or condition for which the patient is being tested. Laboratories should consider available guidelines for requesting and obtaining this additional information and determine circumstances in which more specific patient information is needed for particular genetic tests (126,127). Although this information is not specified in CLIA, the regulations provide laboratories the flexibility to determine and solicit relevant and necessary information for a specific test (42 CFR §493.1241[c][8]). The recommended test request components also are consistent with many voluntary professional and accreditation guidelines (12--14).

Documentation of informed consent. Methods for indicating and documenting informed consent on a test request might include a statement, text box, or check-off box on the test request form to be signed or checked by the test requestor a separate form to be signed as part of the test request or another method that complies with applicable requirements and adheres to professional guidelines. In addition, when state or local laws or regulations specify that patient consent must be obtained regarding the use of tested specimens for quality assurance or other purposes, the test request must include a way for the test requestor to indicate the decision of the patient. Laboratories also might determine that other situations merit documentation of consent before testing.

Specimen Submission, Handling, and Referral

CLIA requires laboratories to establish and follow written policies and procedures for patient preparation, specimen collection, specimen labeling (including patient name or unique patient identifier and, when appropriate, specimen source), specimen storage and preservation, conditions for specimen transportation, specimen processing, specimen acceptability and rejection, and referral of specimens to another laboratory (42 CFR §493.1242). If a laboratory accepts a referral specimen, appropriate written instructions providing information on specimen handling and submission must be available to the laboratory clients. The following recommendations are intended to help laboratories that perform molecular genetic testing meet general CLIA requirements and to provide additional guidelines on quality assurance measures for specimen submission, handling, and referral for molecular genetic testing. Before test selection and ordering, laboratories that perform molecular genetic testing should provide their users with instructions on specimen collection, handling, transport, and submission. Information on appropriate collection, handling, and submission of specimens for molecular genetic tests should include the following:

  • Appropriate type and amount of specimens to be collected
  • Collection container or device to be used (e.g., tubes with specific anticoagulants, specific cups or tubes containing sterile tissue culture media, or buccal swabs)
  • Special timing of specimen collection (if required)
  • Specimen preparation and handling before submission to the laboratory (e.g., dissection of chorionic villus sampling and safe disposal of materials used in specimen collection)
  • Specimen stability information, including the time frame beyond which the stability and integrity of a specimen or the analytes to be detected in a specimen might be compromised
  • Specimen transport conditions (e.g., ambient temperature, refrigeration, and immediate delivery)
  • Reasons for rejection of specimens

Criteria for specimen acceptance or rejection. Laboratories should have written criteria for acceptance or rejection of specimens for the molecular genetic tests they perform and should promptly notify the authorized person when a specimen meets the rejection criteria and is determined to be unsuitable for testing. The criteria should include information on determining the existence of and addressing the following situations:

  • Improper handling or transport of specimens
  • Specimen exposure to temperature extremes that affect sample stability or integrity
  • Insufficient specimen volume or amount
  • Use of inappropriate anticoagulants or media, specimen degradation, or inappropriate specimen types
  • Commingled specimens or possible contamination of specimens that might affect results of molecular amplification procedures
  • Specimens that are mislabeled or lack unique identifiers
  • Lack of unique identifiers on the test request form
  • Lack of other information needed to determine whether the specimen or test requested is appropriate for answering the clinical question

Retention and exchange of information throughout the testing process. Information on test requests and test reports is a particularly important component of the complex communication between genetic testing laboratories and their users. Laboratories should have policies and procedures in place to ensure that information needed for selection of appropriate test methods, test performance, and results interpretation is retained throughout the entire molecular genetic testing process. This recommendation is based on CLIAC recognition of instances in which information on test requests or test reports was removed by electronic or other information systems during specimen submission, results reporting, or test referral. CLIA requires laboratories to ensure the accuracy of test request or authorization information when transcribing or entering the information into a record system or a laboratory information system (42 CFR §493.1241[e]). For molecular genetic tests, information on test requests and test reports should be retained accurately and completely throughout the testing process.

Specimen referral. CLIA requires laboratories to refer specimens for any type of patient testing to CLIA-certified laboratories or laboratories that meet equivalent requirements as determined by CMS (42 CFR §493.1242[c]). Examples of laboratories that meet equivalent requirements include Department of Veterans Affairs laboratories, Department of Defense laboratories, and laboratories in CLIA-exempt states.

Preanalytic Systems Quality Assessment

Laboratories must have written policies and procedures for assessing and correcting problems identified in test requests, specimen submission, and other preanalytic steps of molecular genetic testing (42 CFR §493.1249). The preanalytic systems assessment for molecular genetic testing should include the following practices:

  • Establish and follow procedures for ensuring the testing requested meets the clinical expectation to the extent possible with available information. Laboratories should seek clarification for test requests that are unclear or lack critical information, are submitted with inappropriate specimens, or are inconsistent with the expected use of test results. For example, if a test request has no information on patient race/ethnicity or family history information, but this information is needed to determine the proper test method or mutations to be detected, the laboratory should contact the test requestor and obtain the information. In addition, if the ICD code provided does not match the test requested, the laboratory should consider the code and the additional information provided, including the indications for the test request, and contact the test requestor for clarification if needed.
  • Follow written policies and procedures to ensure that information necessary for selection of appropriate test methods, performance, and results interpretation is retained throughout specimen submission, reporting of test results, and specimen referral. Information received by the laboratory should be monitored to ensure completeness and accuracy efforts should be made to correct the problems and prevent recurrence. If a laboratory realizes that needed information has been automatically removed electronically from test requests during specimen submission or referral, the laboratory should contact the test requestor or referring laboratory to obtain the information and establish effective procedures to ensure the needed information is retained during the entire testing process.

The Analytic Testing Phase

Establishment and Verification of Performance Specifications

CLIA requires laboratories to establish or verify the analytic performance of all nonwaived tests and test systems before introducing them for patient testing and to determine the calibration and control procedures of tests based on the performance specifications verified or established. Before reporting patient test results, each laboratory that introduces an unmodified, FDA-cleared or FDA-approved test system must 1) demonstrate that the manufacturer-established performance specifications for accuracy, precision, and reportable range of test results can be reproduced and 2) verify that the manufacturer-provided reference intervals (or normal values) are appropriate for the laboratory patient population (42 CFR §493.1253). Laboratories are subject to more stringent requirements when introducing 1) FDA-cleared or FDA-approved test systems that have been modified by the laboratory, 2) laboratory-developed tests or test systems that are not subject to FDA clearance or approval (e.g., standardized methods and textbook procedures), or 3) test systems with no manufacturer-provided performance specifications. In these instances, before reporting patient test results, laboratories must conduct more extensive procedures to establish applicable performance specifications for accuracy, precision, analytic sensitivity, analytic specificity reportable range of test results reference intervals, or normal values and other performance characteristics required for test performance.

Although laboratories that perform molecular genetic testing for heritable diseases and conditions must comply with these general CLIA requirements, additional guidelines are needed to assist with establishment and verification of performance specifications for these tests. The recommended laboratory practices that follow are primarily intended to provide specific guidelines for establishing performance specifications for laboratory-developed molecular genetic tests to ensure valid and reliable test performance and interpretation of results. The recommendations also might be used by laboratories to verify performance specifications of unmodified FDA-cleared or FDA-approved molecular genetic test systems to be introduced for patient testing.

Factors that should be considered when developing performance specifications for molecular genetic tests include the intended use of the test target genes, sequences, and mutations intended patient populations test methods and samples to be used (99). The following five steps should be considered general principles for establishing performance specifications of each new molecular genetic test:

  • Conduct a review of available scientific studies and pertinent references.
  • Define appropriate patient populations for which the test should be performed.
  • Select the appropriate test methodology for the disease or condition being evaluated.
  • Establish analytic performance specifications and determine quality control procedures using the appropriate number, type, and variety of samples.
  • Ensure that test results and their implications can be interpreted for an individual patient or family and that the limitations of the test are defined and reported.

Samples for establishment of performance specifications. Establishment of performance specifications should be based on an adequate number, type, and variety of samples to ensure that test results can be interpreted for specific patient conditions and that the limitations of the testing and test results are known. When selecting samples, the following factors should be considered:

  • The prevalence of the disease and the mutations or variants being evaluated. Laboratories should not set lower standards for rare diseases or rare mutations samples should be adequate and appropriate for establishing test performance specifications and defining limitations.
  • Inclusion of samples that represent each type of patient specimen expected for the assay (e.g., blood, buccal swabs, dried blood spots, fresh or frozen tissue, paraffin-embedded tissue, or prenatal specimens).
  • Inclusion of samples that represent each of the possible reportable results (or genotypes). For a multiplex genetic test or a test using targeted detection methods to evaluate multiple nucleic acid targets, all the mutations or variants to be detected should be included in the performance establishment. In certain situations, naturally occurring samples that contain target genotypes are difficult to obtain for rare mutations and variants, or a disease is not associated with common mutations in these instances, the alternative control samples and alternative control procedures that will be used should be included in the establishment of performance specifications.
  • Performance specifications to be established.
  • Control materials, calibration materials, and other reference materials needed for the test procedures.

Analytic performance specifications. Laboratories should determine performance specifications for all of the following analytic performance characteristics for molecular genetic tests that are not cleared or approved by FDA before introducing the tests for patient testing:

  • Accuracy
  • Precision
  • Analytic sensitivity
  • Analytic specificity
  • Reportable range of test results for the test system
  • Reference range or normal values
  • Other performance characteristics required or necessary for test performance

Accuracy. Accuracy is commonly defined as "closeness of the agreement between the result of a measurement and a true value of the measurand" (128). For qualitative molecular genetic tests, laboratories are responsible for verifying or establishing the accuracy of the method used to identify the presence or absence of the analytes being evaluated (e.g., mutations, variants, or other targeted nucleic acids). Accuracy might be assessed by testing reference materials, comparing test results against results of a reference method, comparing split-sample results with results obtained from a method shown to provide clinically valid results, or correlating research results with the clinical presentation when establishing a test system for a new analyte, such as a newly identified disease gene (96).

Precision. Precision is defined as "closeness of agreement between independent test results obtained under stipulated conditions" (129). Precision is commonly determined by assessing repeatability (i.e., closeness of agreement between independent test results for the same measurand under the same conditions) and reproducibility (i.e., closeness of agreement between independent test results for the same measurand under changed conditions). Precision can be verified or established by assessing day-to-day, run-to-run, and within-run variation (as well as operator variance) by repeat testing of known patient samples, quality control materials, or calibration materials over time (96).

Analytic sensitivity. Practice guidelines vary in their definitions of analytic sensitivity certain guidelines consider analytic sensitivity to be the ability of an assay to detect a given analyte, or the lower limit of detection (LOD) (93), whereas guidelines for molecular genetic testing for heritable diseases consider analytic sensitivity to be "the proportion of biological samples that have a positive test result or known mutation and that are correctly classified as positive" (12). However, determining the LOD of a molecular genetic test or test system is often needed as part of the performance establishment and verification (93). To avoid potential confusion among users and the general public in understanding the test performance and test results, laboratories should review and follow applicable professional guidelines before testing is introduced and ensure the guidelines are followed consistently throughout performance establishment and verification and during subsequent patient testing. Analytic sensitivity should be determined for each molecular genetic test before the test is used for patient testing.

Analytic specificity. Analytic specificity is generally defined as the ability of a test method to determine only the target analytes to be detected or measured and not the interfering substances that might affect laboratory testing. Interfering substances include factors associated with specimens (e.g., specimen hemolysis, anticoagulant, lipemia, and turbidity) and factors associated with patients (e.g., clinical conditions, disease states, and medications) (96). Laboratories must document information regarding interfering substances and should use product information, literature, or the laboratory's own testing (96). Accepted practice guidelines for molecular genetic testing, such as those developed by ACMG, CAP, and CLSI, define analytic specificity as the ability of a test to distinguish the target sequences, alleles, or mutations from other sequences or alleles in the specimen or genome being analyzed (12--14). The guidelines also address documentation and determination of common interfering substances specific for molecular detection (e.g., homologous sequences, contaminants, and other exogenous or endogenous substances) (12--14). Laboratories should adhere to these specific guidelines in establishing or verifying analytic specificity for each of their molecular genetic tests.

Reportable range of test results. As defined by CLIA, the reportable range of test results is "the span of test result values over which the laboratory can establish or verify the accuracy of the instrument or test system measurement response" (36). The reportable range of patient test results can be established or verified by assaying low and high calibration materials or control materials or by evaluating known samples of abnormally high and low values (96). For example, laboratories should assay quality control or reference materials, or known normal samples, and samples containing mutations to be detected for targeted mutation analyses. For analysis of trinucleotide repeats, laboratories should include samples representing the full range of expected allele lengths (130).

Reference range, or reference interval (i.e., normal values). As defined by CLIA, a reference range, or reference interval, is "the range of test values expected for a designated population of persons (e.g., 95% of persons that are presumed to be healthy [or normal])" (36). The CMS Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services provides general guidelines regarding the use of manufacturer-provided or published reference ranges appropriate for the patient population and evaluation of an appropriate number of samples to verify manufacturer claims or published reference ranges (96). For all laboratory-developed tests, the laboratory is responsible for establishing the reference range appropriate for the laboratory patient population (including demographic variables such as age and sex) and specimen types (96). For molecular genetic tests for heritable diseases and conditions, normal values might refer to normal alleles in targeted mutation analyses or the reference sequences for sequencing assays. Laboratories should be aware that advances in knowledge and testing technology might affect the recognition and documentation of normal sequences and should keep an updated database for the molecular genetic tests they perform.

Quality control procedures. CLIA requires laboratories to determine the calibration and control procedures for nonwaived tests or test systems on the basis of the verification or establishment of performance specifications for the tests (42 CFR §493.1253[b][3]). Laboratories that perform molecular genetic tests must meet these requirements and, for every molecular genetic test to be introduced for patient testing, should consider the recommended quality control practices.

Documentation of information on clinical validity. Laboratories should ensure that the molecular genetic tests they perform are clinically usable and can be interpreted for specific patient situations. Laboratory responsibilities for clinical validity include the following:

  • Documenting information regarding clinical validity (including clinical sensitivity, clinical specificity, positive predictive value, and negative predictive value) of all genetic tests the laboratory performs from available information sources (e.g., published studies and professional practice guidelines)
  • Providing clinical validity information to users of laboratory services before tests are selected and specimens submitted
  • If clinical validity information is not available from published sources, establishing clinical sensitivity, clinical specificity, and predictive values on the basis of internal study results
  • Documenting whether the clinical claims in the references or information sources used can be reproduced in the laboratory and providing this information to users, including indicating test limitations in all test reports
  • Informing users of changes in clinical validity values as a result of knowledge advancement
  • Specifying that the responsibilities of the laboratory director and technical supervisor include ensuring appropriate documentation and reporting of clinical validity information for molecular genetic tests performed by the laboratory

Although CLIA regulations do not include validation of clinical performance specifications of new tests or test systems, laboratories are required to ensure that the tests being performed meet clinical expectations. For tests of high complexity, such as molecular genetic tests, laboratory directors and technical supervisors are responsible for ensuring that the testing method is appropriate for the clinical use of the test results and can provide the quality of results needed for patient care (36). Laboratory directors and clinical consultants must ensure laboratory consultations are available for laboratory clients regarding the appropriateness of the tests ordered and interpretation of test results (36). Documentation of available clinical validity information helps laboratories that perform molecular genetic testing to fulfill their responsibilities for consulting with health-care professionals and other users of laboratory services, especially regarding tests that evaluate germline mutations or variants that might be performed only once during a patient's lifetime.

Establishing clinical validity is a continuous process and might require extended studies and involvement of many disciplines (38). The recommendations in this report emphasize the responsibility of laboratories that perform molecular genetic testing to document available information from medical and scientific research studies on the intended patient populations to be able to perform testing and provide results interpretation appropriate for specific clinical contexts. Laboratory directors are responsible for using professional judgment to evaluate the results of such studies as applied to newly discovered gene targets, especially those of a predictive or incompletely penetrant nature, in considering potential new tests. The recommendations in this report are consistent with the voluntary professional and accreditation guidelines of ACMG, CLSI, and CAP for molecular genetic testing (12--14,93,94).

Control Procedures

General quality control practices. The analytic phase of molecular genetic testing often includes the following steps: specimen processing nucleic acid extraction, preparation, and assessment enzymatic reaction or amplification analyte detection and recording of test results. Laboratories that perform molecular genetic testing must meet the general CLIA requirements for nonwaived testing (42 CFR §493.1256) (36), including the following applicable quality control requirements:

  • Laboratories must have control procedures in place to monitor the accuracy and precision of the entire analytic process for each test system.
  • The number and type of control materials and the frequency of control procedures must be established using applicable performance specifications verified or established by the laboratory.
  • Control procedures must be in place for laboratories to detect immediate errors caused by test system failure, adverse environmental conditions, and operator performance to monitor the accuracy and precision of test performance over time.
  • At least once each day that patient specimens are tested, the laboratory must include the following:

--- At least two control materials of different concentrations for each quantitative procedure

--- A negative control material and a positive control material for each qualitative procedure

--- A negative control material and a control material with graded or titered reactivity, respectively, for each test procedure producing graded or titered results

--- Two control materials, including one that is capable of detecting errors in the extraction process, for each test system that has an extraction phase

--- Two control materials for each molecular amplification procedure and, if reaction inhibition is a substantial source of false-negative results, a control material capable of detecting the inhibition

  • If control materials are not available, the laboratory must have an alternative method for detecting immediate errors and monitoring test system performance over time the performance of the alternative control procedures must be documented.

Specific quality control practices. Specific quality control practices are necessary for ensuring the quality of molecular genetic test performance. The following recommendations include specific guidelines for meeting the general CLIA quality control requirements and additional measures that are more stringent or explicit than the CLIA requirements for monitoring and ensuring the quality of the molecular genetic testing process:

  • When possible, include quality control samples that are similar to patient specimens to monitor the quality of all analytic steps of the testing process.
  • Include an extraction control for any test that has a nucleic acid extraction step to monitor and determine the quality and integrity of the specimens, evaluate whether the yield of nucleic acid extraction is appropriate for the test, and detect the presence of inhibitors.
  • Validate and monitor sampling instruments to ensure no carryover (i.e., contamination) occurs between sample testing on automated instruments. For example, if DNA extraction is performed by an automated system, the positioning and regular testing of appropriate controls should be included in the quality control procedures. Experiments in which samples containing target nucleic acids are interspaced with samples with no template nucleic acids (i.e., checkerboard experiments) might be considered as a method for monitoring and detecting carryover.
  • Perform control procedures each time patient specimens are tested.
  • Ensure that the type and variety of the control materials included in tests are as comprehensive as possible, representing the genotypes expected for the patient population according to the prevalence of the disease and frequency of the mutations or variants. For example, either a heterozygous sample or a normal sample and a homozygous mutant sample might be considered sufficient for a test being used to detect a single mutation. For a sequencing assay performed for a known mutation, such as testing a patient's family member for a mutation that the laboratory previously detected in the patient, the laboratory should include the patient's sample as a positive control for the testing.

Alternative control procedures. Ideally, laboratories should use control materials to monitor the entire testing process, but such materials are not always practical or available. Appropriate alternative control procedures depend on the specific test and the control materials needed. Following are examples of accepted alternative control procedures when control materials are not available:

  • If the positive control material for a specific mutation is not available for a targeted mutation analysis, alternative control procedures could include direct sequencing or testing of the patient sample by a reference laboratory to confirm the finding before reporting the test result.
  • Inclusion of a normal control is important for sequencing procedures. A normal control could be a tested, well-characterized patient sample that contains the reference sequence or a sample that contains subcloned reference sequence. If a positive control is not available, alternative control procedures could include bidirectional sequencing, which should use a separately extracted nucleic acid sample (if possible).
  • If having positive controls for each variant or mutation is impractical in testing that detects multiple mutations or variants, rotating all positive controls within a time frame that is reasonable and effective for monitoring test performance over time and detecting immediate errors is important.
  • If a commercial test system provides some but not all of the controls needed for testing, the laboratory must perform and follow the manufacturer recommendations for control testing and should determine the additional control procedures (including the number and types of control materials and the frequency of testing them) necessary for monitoring and ensuring the quality of test performance (36,96).
  • Laboratories must have an alternative mechanism capable of monitoring DNA extraction and the preceding analytic steps if 1) purified DNA samples are used as control materials for circumstances in which incorporation of an extraction control is impractical or 2) when testing is performed for a rare disease or rare variants for which no control material is available for the extraction phase. For example, testing patient specimens for an internal control sequence (e.g., a housekeeping gene or a spiked-in control sequence) might allow for monitoring of the sample quality and integrity, the presence of inhibitors, and proper amplification (12,93). A positive control, or a control sample capable of monitoring the ability of a test system to detect the nucleic acid targets, should be tested periodically and carried through the extraction step to monitor and verify the performance of the test system.

The CMS Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services provides general guidelines for alternative control procedures and encourages laboratories to use multiple mechanisms for ensuring testing quality (96). Following are examples of procedures that, when applicable, should be followed by laboratories that perform molecular genetic testing:

  • Split specimens for testing by another method or in another laboratory.
  • Include previously tested patient specimens (both positive and negative) as surrogate controls.
  • Test each patient specimen in duplicate.
  • Test multiple types of specimens from the same patient (e.g., saliva, urine, or serum).
  • Perform serial dilutions of positive specimens to confirm positive reactions.
  • Conduct an additional supervisory review of results before release.

Unidirectional workflow for molecular amplification procedures. CLIA requires laboratories to have procedures in place to monitor and minimize contamination during the testing process and to ensure a unidirectional workflow for amplification procedures that are not contained in closed systems (42 CFR §493.1101) (36). In this context, a closed system is a test system designed to be fully integrated and automated to purify, concentrate, amplify, detect, and identify targeted nucleic acid sequences. Such a modular system generates test results directly from unprocessed samples without manipulation or handling by the user the system does not pose a risk for cross-contamination because amplicon-containing tubes and compartments reamain completely closed during and after the testing process. For example, according to CLIA regulations, an FDA-cleared or FDA-approved test system that contains amplification and detection steps in sealed tubes that are never opened or reopened during or after the testing process and that is used as provided by the manufacturer (i.e., without any modifications) is considered a closed system.

The requirement for a unidirectional workflow, which includes having separate areas for specimen preparation, amplification, product detection, and reagent preparation, applies to any testing that involves molecular amplification procedures. The following recommendations provide more specific guidelines for laboratories that perform molecular genetic testing for heritable diseases and conditions using amplification procedures that are not in a closed system:

  • Include at least one no-template control (NTC) sample each time patient specimens are assayed. Molecular amplification procedures are especially sensitive to carryover and cross-contamination. Although laboratories must ensure a unidirectional workflow and might use reagents and other methods to prevent or minimize carryover, inclusion of NTC samples in these procedures is essential for monitoring the test procedures and indicating whether measures taken to minimize cross-contamination are effective. At a minimum, the NTC sample should be included in the amplification step and carried through the subsequent steps detecting test results. When possible, an NTC sample also should be included in the extraction step, in addition to the NTC sample for the amplification. If multiple units (e.g., multiple 96-well plates) are used in a run of patient specimen testing, an NTC sample should be included in each unit of the test run if the test system allows it.
  • Determine the order of samples, including the number and positions of the NTC and other control samples, to adequately monitor carryover contamination. For testing performed in multiple units, the number and positions of NTC samples also may be used for unambiguous identification of each unit.
  • Ensure that specific procedures are in place to monitor the unidirectional workflow and to prevent cross-contamination for tests using successive amplification procedures (e.g., amplification of nucleic acid targets from a previous polymerase chain reaction [PCR] or nested PCR) if reaction tubes are opened after amplification for subsequent manipulation with the amplicons. Additives that destroy amplicons from previous PCR reactions also may be used.

Laboratories should recognize that methods such as PCR amplification, whole genome amplification, or subcloning to prepare quality control materials might be a substantial source of laboratory contamination. These laboratories should have the following specific procedures to monitor, detect, and prevent cross-contamination:

  • Separation of the workflow of generating and preparing synthetic or amplified products for use as control materials from the patient testing process. To prevent laboratory contamination, control materials should be processed and stored separately from the areas for preparation and storage of patient specimens and testing reagents.
  • Regular testing of appropriate control samples at a frequency adequate to monitor cross-contamination.

These practices also should be considered by laboratories that purchase amplified materials for use as control materials, calibration materials, or competitors.

Proficiency Testing and Alternative Performance Assessment

Proficiency testing is an important tool for assessing laboratory competence, evaluating the laboratory testing process, and providing education for the laboratory personnel. For certain analytes and testing specialties for which CLIA regulations specifically require proficiency testing, proficiency testing is provided by private-sector and state-operated programs that are approved by HHS because they meet CLIA standards (42 CFR Part 493). These approved programs also may provide proficiency testing for genetic tests and other tests that are not on the list of regulated analytes and specialties (131). Although the CLIA regulations do not have proficiency testing requirements specific for molecular genetic tests, laboratories that perform genetic tests must comply with the general requirements for alternative performance assessment for any test or analyte not specified as a regulated analyte to, at least twice annually, verify the accuracy of any genetic test or procedure they perform (42 CFR §493.1236[c]). Laboratories can meet this requirement by participating in available proficiency testing programs for the genetic tests they perform (132).

The following recommended practices provide more specific and stringent measures than the current CLIA requirements for performance assessment of molecular genetic testing. The recommendations should be considered by laboratories that perform molecular genetic testing to monitor and evaluate the ongoing quality of the testing they perform:

  • Participate in available proficiency testing, at least twice per year, for each molecular genetic test the laboratory performs. Proficiency testing is available for a limited number of molecular genetic tests (e.g., fragile X syndrome, factor V Leiden thrombophilia, and cystic fibrosis) (Appendix C). Laboratories that perform molecular genetic testing should regularly review information on the development of additional proficiency testing programs and ensure participation as new programs become available.
  • Test analyte-specific or disease-specific proficiency testing challenges with the laboratory's regular patient testing workload by personnel who routinely perform the tests in the laboratory (as required by CLIA for regulated analytes).
  • Evaluate proficiency testing results reported by the proficiency testing program and take steps to investigate and correct disparate results. The corrective actions to be taken after disparate proficiency testing results should include re-evaluation of previous patient test results and, if necessary, of retained patient specimens that were previously tested.

Proficiency testing samples. When possible, proficiency testing samples should resemble patient specimens at a minimum, samples resembling patient specimens should be used for proficiency testing for the most common genetic tests. When proficiency testing samples are provided in the form of purified DNA, participating laboratories do not perform all the analytic steps that occur during the patient testing process (e.g., nucleic acid extraction and preparation). Such practical limitations should be recognized when assessing proficiency testing performance. Laboratories are encouraged to enroll in proficiency testing programs that examine the entire testing process, including the preanalytic, analytic, and postanalytic phases.

Alternative performance assessment. For molecular genetic tests for which no proficiency testing program is available, alternative performance assessments must be performed at least twice per year to meet the applicable requirements of CLIA and requirements of certain states and accrediting organizations. The following recommendations should be considered when conducting alternative performance assessments:

  • Although no data are available to determine whether alternative performance assessments are as effective as proficiency testing, professional guidelines (e.g., from CLSI and CAP) provide information on acceptable alternative performance assessment approaches (14,61). Laboratories that perform molecular genetic tests for which no proficiency testing program is available should adhere to these guidelines.
  • Laboratories should ensure that alternative assessments reflect the test methods involved in performing the testing and that the number of samples in each assessment is adequate to verify the accuracy and reliability of test results.
  • Ideally, alternative assessments should be performed through interlaboratory exchange (Appendix C) or using externally derived materials, because external quality assessments might detect errors or problems that would not be detected by an internal assessment.
  • When interlaboratory exchange or obtaining external materials is not practical (e.g., testing for rare diseases, testing performed by only one laboratory, patented testing, or unstable analytes such as RNA or enzymes), laboratories may consider options such as repeat testing of blinded samples, blind testing of materials with known values, exchange with either a research facility or a laboratory in another country, splitting samples with another instrument or method, or interlaboratory data comparison (96).

Various resources for proficiency testing and external quality assessment (60,133,134) and for facilitating interlaboratory sample exchanges (135,136) are available to help laboratories consider approaches to meeting the proficiency testing and alternative performance assessment needs of their molecular genetic testing (Appendix C).

The Postanalytic Testing Phase

Molecular Genetic Test Reports

Content. Molecular genetic test reports must comply with the CLIA general test report requirements (42 CFR §493.1291) and should include the additional information that follows to ensure accurate understanding and interpretation of test results. CLIA requires that test reports for nonwaived testing include the following information:

  • Patient name and identification number or a unique patient identifier and identification number
  • Name and address of laboratory where the test was performed
  • Test report date
  • Test performed
  • Specimen source (when appropriate)
  • Test results and (if applicable) units of measurement or interpretation
  • Information regarding the condition and disposition of specimens that did not meet laboratory criteria for acceptability

For in-house developed tests using analyte-specific reagents, test reports must include the following statement: "This test was developed and its performance characteristics determined by (Laboratory Name). It has not been cleared or approved by the U.S. Food and Drug Administration" (21 CFR §809.30[e]).

Test reports of molecular genetic testing for heritable conditions should include the following additional information to ensure accurate results interpretation, patient management, and, the ordering of any needed additional tests by persons receiving or using the test results:

  • Patient name and any other necessary unique identifiers. The patient name should be included on the test report when possible, in addition to other necessary unique identifiers.
  • Patient date of birth
  • Indication for testing
  • Date and (if applicable) time of specimen collection and arrival in laboratory
  • Name of referring physician or authorized person who ordered the test
  • Test method, including the nucleic acid targets of the test. Laboratories should indicate on the test report the test method used to perform the test, including the nucleic acid targets of the test and the analytic method (e.g., targeted mutation detection or DNA sequence analysis).
  • Test performance specifications and limitations. CLIA requires laboratories to provide clients, on request, with a list of tests they perform and the required performance specifications (42 CFR §493.1291[e]). For molecular genetic tests, information on performance specifications and limitations (e.g., statement on the intended use and the technical limitations of the test methodology) should be essential components of the test report rather than information that is available only when requested.
  • Test results in current recommended standard nomenclature. Molecular genetics nomenclature is evolving, and laboratories or users of laboratory services might not be familiar with the new nomenclature. Therefore, test results should be provided in current recommended standard nomenclature, which should include clarifications and commonly used terms (if the terms differ from the current recommended terms) and should indicate the genotypes detected. For certain genetic variants or diseases associated with more than one common version of nomenclature (e.g., cytochrome P450 [CYP] genes or hemoglobinopathies), laboratories might need to report all versions to ensure that test results are understandable and to avoid unnecessary repetition of the testing solely because the nomenclature varies or has changed over time. If no mutation is detected, the test report should indicate "no mutation detected" rather than "normal."
  • Interpretation of test results. Laboratories are required by CLIA to include interpretation of test results on test reports (if applicable). However, results interpretation should be included in all test reports of molecular genetic testing for heritable diseases and conditions. Laboratories should provide information on interpretation of test results in a clinically relevant manner that is relative to the purpose for the testing and should explain how technical limitations might affect the clinical use of the test results. When appropriate and necessary, test results can be explained in reference to family members (e.g., mutations previously detected in a family member that was used for selection of the test method) to ensure appropriate interpretation of results and understanding of their implications by the persons receiving or using the test results.
  • References to literature (if applicable)
  • Recommendation for genetics consultation (when appropriate). A genetics consultation might encompass genetic services (including genetic counseling) provided by trained, qualified genetics professionals (e.g., genetic counselors, clinical geneticists, or other qualified professionals) for health-care providers, patients, or family members at risk for the condition.
  • Implications of test results for relatives or family members who might benefit from the information (if applicable)
  • Statement indicating that the test results and interpretation are based on current knowledge andtechnology

Updates and revisions. CLIA requires laboratories to provide pertinent updates on testing information to clients when changes occur that affect the test results or interpretation of test results (42 CFR §493.1291[e]). Because the field of molecular genetic testing is evolving rapidly, laboratories should consider the following:

  • Keep an up-to-date database for the molecular genetic tests performed in the laboratory, and provide updates to users when knowledge advancement affects performance specifications, interpretation of test results, or both.
  • Provide a revised test report if the interpretation of the original analytic result changes because of advances in knowledge or testing technology. Indications for providing revised test reports include the following:

--- A better interpretation is available on a previously detected variant.

--- Interpretation of previous test results has changed (e.g., a previously determined mutation is later recognized as a benign variant or polymorphism or vice versa).

Molecular genetic tests for germline mutations or variants or for other heritable conditions often are one-time tests, with results that can have life-time implications for the patients and family members. Decisions regarding health-care management should be made with consideration of changes or improvements in the interpretation of genetic test results as testing technology and knowledge advance. However, practical limitations, such as the logistical difficulty of recontacting previous users of laboratory services, also should be considered. Laboratories that perform molecular genetic testing for heritable diseases and conditions should have procedures in place that adhere to accepted professional practice guidelines regarding the duty to recontact previous users and should make a good-faith effort to provide updates and revisions to previous test reports, when appropriate (137). When establishing these procedures, laboratories also might consider the retention time frame of their molecular genetic test reports.

Signatures. Review of molecular genetic test reports by trained qualified personnel, before reports are released, is critical. The review should be appropriately documented with written or electronic signatures or by other methods. Laboratories should determine which persons should review and sign the test reports in accordance with personnel competency and responsibilities.

Format, style, media, and language. Laboratories should assess the needs of laboratory users when determining the format, style, media, and language of molecular genetic test reports. The language used, which includes terminology and nomenclature, should be understandable by nongeneticist health professionals and other specific users of the test results. This practice should be part of the laboratory quality management policies. Test reports should include all necessary information, be easy to understand, and be structured in a way that encourages users read the entire report, rather than just a positive or negative indication. Following the format recommended in accepted practice guidelines should help ensure that the reports are structured effectively (12--14,49,93,94,100).

Retention of Reports, Records, and Tested Specimens

Reports. CLIA requires laboratories to retain or have the ability to retrieve a copy of an original test report (including final, preliminary, and corrected reports) for at least 2 years after the date of reporting and to retain pathology test reports for at least 10 years after the date of reporting (42 CFR §493.1105). A longer retention time frame than required by CLIA is warranted for reports of molecular genetic tests for heritable diseases and conditions. These test reports should be retained for at least 25 years after the date the results are reported.

Retaining molecular genetic test reports for a longer time frame is recommended because the results can have long-term, often lifetime, implications for patients and their families, and future generations might need the information to make health-related decisions. In addition, advances in testing technology and increased knowledge of disease processes could change the interpretation of the original test results, enable improved interpretation of test results, or permit future retesting with greater sensitivity and accuracy. Laboratories need the ability to retrieve previous test reports, which are valuable resources for conducting quality assessment activities, helping patients and family members make health decisions, and managing the health care of the patient and family members. As laboratories that perform molecular genetic testing for heritable diseases and conditions review and update policies and procedures for report retention, they should consider the financial ramifications of the policies, as well as technology and space concerns. Laboratories may consider retaining test reports electronically, on microfilms, or by other methods but must ensure that all of the information on the original reports is retained and that copies (whether electronic or hard copies) of the original reports can be retrieved.

The laboratory policies and procedures for test report retention must comply with applicable state laws and other requirements (e.g., of accrediting organizations if the laboratory is accredited) and should follow practice guidelines developed by recognized professional or standard-setting organizations. If state regulations require retention of genetic test reports for >25 years after the date of results reporting, laboratories must comply. Laboratories also might decide that retaining reports for >25 years is necessary for molecular genetic test reports for heritable diseases and conditions to accommodate patient testing needs and ongoing quality assessment activities.

Records. CLIA requires laboratories to retain records of patient testing, including test requests and authorizations, test procedures, analytic systems records, records of test system performance specifications, proficiency testing records, and quality system assessment records, for a minimum of 2 years (42 CFR §493.1105) these requirements apply to molecular genetic testing. Retention policies and procedures must also comply with applicable state laws and other requirements (e.g., of accrediting organizations if the laboratory is accredited). Laboratories should ensure that electronic records are accessible.

Tested specimens. CLIA requires laboratories to establish and follow written policies and procedures that ensure positive identification and optimum integrity of patient specimens from the time of collection or receipt in the laboratory through completion of testing and reporting of test results (42 CFR §493.1232). Depending on sample stability, technology, space, and cost, tested specimens for molecular genetic tests for heritable conditions should be retained as long as possible after the completion of testing and reporting of results. At a minimum, tested patient specimens that are stable should be retained until the next proficiency testing or the next alternative performance assessment to allow for identification of problems in patient testing and for corrective action to be taken. Tested specimens also might be needed for testing of current or future family members and for more definitive diagnosis as technology and knowledge evolve. A laboratory specimen retention policy should consider the following factors:

  • Type of specimens retained (e.g., whole blood or DNA samples)
  • Analytes tested (e.g., DNA, RNA, or both)
  • Test results or the genotypes detected. (If only abnormal specimens are retained, identifying false-negative results at a later date will be difficult. This practice also might introduce bias if a preponderance of samples with abnormal test results is used to verify or establish performance specifications for future testing.)
  • Test volume
  • New technologies that might not produce residual specimens

The laboratory director is responsible for ensuring that the laboratory policies and procedures for specimen retention comply with applicable federal, state, and local requirements (including laboratory accreditation requirements, if applicable) and are consistent with the laboratory quality assurance and quality assessment activities. In circumstances in which required patient consent is not provided with the test request, the laboratory should 1) notify the test requestor and 2) determine the time frame after which the test request might be rejected and the specimen discarded because of specimen degradation or deterioration. Laboratory specimen retention procedures should be consistent with patient decisions.

Laboratory Responsibilities Regarding Authorized Persons

CLIA regulations define an authorized person as a person authorized by state laws or regulations to order tests, receive test results, or both. Laboratories must have a written or an electronic test request from an authorized person (42 CFR §493.1241[a]). Laboratories may only release test results to authorized persons, the person responsible for using the test results (if applicable), and the laboratory that initially requested the test (42 CFR §493.1291[f]). Laboratories that perform molecular genetic testing must ensure compliance with these requirements in their policies and procedures for receiving test requests and reporting test results and should ensure that qualified laboratory personnel with appropriate experience and expertise are available to assist authorized persons with test requests and interpretation of test results.

Laboratories must comply with applicable federal, state, and local requirements regarding whether genetic tests may be offered directly to consumers and should use accepted professional guidelines for additional information. The following recommendations will help laboratories meet CLIA requirements (42 CFR §§493.1241[a] and 1291[f]), particularly those related to genetic testing offered directly to consumers:

  • The laboratory that initially accepts a test request (regardless of whether the laboratory performs the testing on-site or refers the patient specimens to another laboratory) is responsible for verifying that the test requestor is authorized by state laws and regulations to do so. Laboratories that receive patient specimens from multiple states or have specimen collection sites in multiple states should keep an updated copy of the requirements of each state regarding authorized persons and review test requests accordingly.
  • Although referral laboratories might be unable to verify that the person submitting the original test request qualifies as an authorized person, the test results may only be released to persons authorized by state laws and regulations to receive the results, the persons responsible for using the test results, and the referring laboratory.

Ensuring Confidentiality of Patient Information

CLIA requires laboratories to ensure confidentiality of patient information throughout all phases of the testing process that are under laboratory control (42 CFR §493.1231). Laboratories should follow more specific requirements and comply with additional guidelines (e.g., the Health Insurance Portability and Accountability Act of 1996 [HIPAA] Privacy Rule, state requirements, accreditation standards, and professional guidelines) to establish procedures and protocols to protect the confidentiality of patient information, including information related to genetic testing. Laboratories that perform molecular genetic testing should establish and follow procedures and protocols that include defined responsibilities of all employees to ensure appropriate access, documentation, storage, release, and transfer of confidential information and prohibit unauthorized or unnecessary access or disclosure.

Information Regarding Family Members

In certain circumstances, information about family members is needed for test performance or should be included in test reports to ensure appropriate interpretation of test results. Therefore, laboratories must have procedures and systems in place to ensure confidentiality of all patient information, including that of family members, in all testing procedures and reports, in compliance with CLIA requirements and other applicable federal, state, and local regulations.

Requests for Test Results to Assist with Providing Health Care for a Family Member

When a health-care provider requests the genetic test information of a patient to assist with providing care for a family member of the patient, the following practices are recommended:

  • Requests should be handled following established laboratory procedures regarding release and transfer of confidential patient information.
  • Laboratories may release patient test information only to the authorized person ordering the test, the persons responsible for using the test results (e.g., health-care providers of the patient designated by the authorized person to receive test results), and the laboratory that initially requested the test. If a health-care provider who provides care for a family member of the patient is authorized to request patient test information, the laboratory should request the patient's authorization before releasing the patient's genetic test results.
  • When patient consent is required for testing, the consent form should include the laboratory confidentiality policies and procedures and describe situations in which test results might be requested by health-care providers caring for family members of the patient.
  • Laboratory directors should be responsible for determining and approving circumstances in which access to confidential patient information is appropriate, as well as when, how, and to whom information is to be released, in compliance with federal, state, and local requirements.

The HIPAA Privacy Rule and CLIA regulations are federal regulations intended to provide minimum standards for ensuring confidentiality of patient information states or localities might have higher standards. Although the HIPAA Privacy Rule allows health-care providers that are covered entities (i.e., health-care providers that conduct certain transactions in electronic form, health-care clearinghouses, and health plans) to use or disclose protected health information for treatment purposes without patient authorization and to share protected health information to consult with other providers to treat a different patient or to refer a patient, the regulation indicates that states or institutions may implement stricter standards to protect the privacy of patients and the confidentiality of patient information (138). Laboratories that perform molecular genetic testing must comply with applicable requirements and follow professional practice guidelines in establishing policies and procedures to ensure confidentiality of patient information, including molecular genetic testing information and test results.

Personnel Qualifications, Responsibilities, and Competency Assessments

Laboratory Director Qualifications and Responsibilities

Qualifications. CLIA requires directors of laboratories that perform high-complexity testing to meet at least one of the following sets of qualifications (42 CFR §493.1443):

  • Be a doctor of medicine or a doctor of osteopathy and have board certification in anatomic or clinical pathology or both
  • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine and have at least 1 year of laboratory training during residency or at least 2 years of experience directing or supervising high-complexity testing
  • Have an earned doctoral degree in a chemical, physical, biological, or clinical laboratory science from an accredited institution and current certification by a board approved by HHS

Directors of laboratories that perform molecular genetic testing for heritable diseases and conditions must meet these qualification requirements. Because CLIA requirements are minimum qualifications, laboratories that perform molecular genetic testing for heritable diseases and conditions should evaluate the tests they perform to determine whether additional knowledge, training, or expertise is necessary for fulfilling the responsibilities of laboratory director.

Responsibilities. CLIA requires directors of laboratories that perform high-complexity testing to be responsible for the overall operation and administration of the laboratory, which includes responsibility for the following (42 CFR §493.1445):

  • Ensuring the quality of all aspects of test performance and results reporting for each test performed in the laboratory
  • Ensuring that the physical and environmental conditions of the laboratory are appropriate and safe
  • Ensuring enrollment in HHS-approved proficiency testing programs
  • Employing a sufficient number of laboratory personnel with appropriate education, experience, training, and competency required for patient testing
  • Establishing policies and procedures for personnel competency assessment and monitoring
  • Specifying the responsibilities and duties of each consultant, supervisor, and testing employee
  • Ensuring compliance with applicable requirements and regulations

Directors of laboratories that perform molecular genetic testing for heritable diseases and conditions must fulfill these CLIA responsibility requirements. In addition, these laboratory directors should be responsible for the following:

  • Ensuring documentation of the clinical validity of any molecular genetic tests the laboratory performs, following the recommended practices
  • Ensuring the specimen retention policy is consistent with the laboratory quality assessment activities

Technical Supervisor Qualifications and Responsibilities

Qualifications. CLIA regulations do not specify qualification requirements for technical supervisors of molecular genetic testing. Technical supervisors of laboratories that perform molecular genetic testing for heritable diseases and conditions should have either one of the following sets of qualifications:

  • Qualifications equivalent to the CLIA qualification requirements for clinical cytogenetics technical supervisors (42 CFR §493.1449[p]), which include either one of the following sets of qualifications:

--- Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine licensed to practice medicine, osteopathy, or podiatry in the state in which the laboratory is located and have 4 years of training or experience (or both) in genetics, 2 of which are in the area of molecular genetic testing for heritable diseases and conditions

--- Have an earned doctoral degree in a chemical, physical, biological, or clinical laboratory science from an accredited institution and have 4 years of training or experience (or both) in genetics, 2 of which are in the area of molecular genetic testing for heritable diseases and conditions

  • Current certification in molecular genetic testing by a board approved by HHS (e.g., the American Board of Medical Genetics [ABMG]) or in molecular genetic pathology by ABMG and the American Board of Pathology

The recommended technical supervisor qualifications are based on the complexity of molecular genetic testing for heritable diseases and conditions and the training, experience, and expertise needed to provide technical supervision for laboratories that perform these tests. Certain laboratories that perform molecular genetic testing for heritable diseases and conditions might have technical supervisors who meet the applicable CLIA qualification requirements for the high-complexity testing their laboratories perform but do not meet the recommended qualifications in this section. These recommended qualifications are not regulatory requirements and are not intended to restrict access to certain molecular genetic tests rather, they should be considered part of recommended laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions. However, because CLIA qualification requirements are intended to be minimum standards, laboratories should assess the tests they perform to determine whether additional qualifications are needed for their technical supervisors to ensure quality throughout the testing process. These recommended qualifications should apply to all high-complexity molecular genetic tests for heritable diseases and conditions.

Responsibilities. CLIA requires technical supervisors of laboratories that perform high-complexity testing to be responsible for the technical and scientific oversight of the laboratories (42 CFR §493.1451). Technical supervisor responsibilities include the following:

  • Selecting testing methods appropriate for the clinical use of the test results
  • Verifying or establishing performance specifications for each test or test system
  • Enrolling the laboratory in HHS-approved proficiency testing programs
  • Establishing and maintaining an appropriate quality control program and ensuring the quality of test performance throughout the testing process
  • Resolving technical problems
  • Ensuring all necessary remedial or corrective actions are taken before patient test results are reported
  • Implementing laboratory personnel competency assessment policies, including evaluating and ensuring the competency of all testing personnel, identifying training needs, ensuring testing personnel receive regular in-service training and education appropriate for the type and complexity of the laboratory services performed, and documenting performance of testing personnel regularly as required

Technical supervisors of laboratories that perform molecular genetic testing for heritable diseases and conditions must fulfill these CLIA responsibility requirements for high-complexity testing. In addition, when deemed necessary by the laboratory director, the responsibilities of the technical supervisor also might include one or more of the following tasks:

  • Assessing the suitability of test requests for the expected clinical use of the test results
  • Ensuring appropriate documentation of clinical validity information before offering new testing for patients
  • Reviewing test results and their interpretation before reporting test results, and if appropriate, signing test reports or providing other documentation of the review on the test reports
  • Providing explanations or clarifications to questions regarding test reports, including test results and interpretation
  • Providing on-site technical supervision for molecular genetic testing

Clinical Consultant Qualifications and Responsibilities

Qualifications. CLIA requires clinical consultants for high-complexity testing to have either one of the following sets of qualifications (42 CFR §493.1455):

  • Be qualified as a laboratory director for high-complexity testing as specified in the regulations
  • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine licensed to practice medicine, osteopathy, or podiatry in the state in which the laboratory is located

These CLIA requirements provide minimum qualifications required for persons who provide clinical consultations for high-complexity testing. For molecular genetic testing for heritable diseases and conditions, clinical consultants should have relevant training, experience, or both in the testing for which they consult. Preferably, clinical consultants for molecular genetic testing for heritable diseases and conditions should have either one of the following sets of qualifications, which are more specific than those required by CLIA:

  • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine and have 2 years of training or experience in genetic testing relevant to the clinical consultation to be provided
  • Have an earned doctoral degree in a relevant discipline, be currently certified by a board approved by HHS, and have 2 years of training or experience in genetic testing relevant to the clinical consultation to be provided

Although genetic counselors who have a master's degree do not meet CLIA requirements for clinical consultants, they perform important functions such as communicating with health-care providers, patients, and family members at risk for certain conditions or diseases regarding test selection, interpretion, of test results, and implications of test results for specific patients and families.

Responsibilities. CLIA requires clinical consultants for high-complexity tests to be responsible for providing consultation to laboratory clients regarding the appropriateness of the testing ordered and the interpretation of test results (42 CFR §493.1457). Persons providing clinical consultation for molecular genetic testing must meet the following CLIA responsibility requirements:

  • Be available to provide consultation to laboratory clients, which includes assisting clients with ordering appropriate tests to meet clinical expectations and discussing the quality of test results and interpretation result
  • Ensure that test reports include pertinent information required for interpretation of specific patient conditions

General Supervisor Qualifications and Responsibilities

Qualifications. CLIA requires general supervisors of laboratories that perform high-complexity tests to have at least one of the following sets of qualifications (42 CFR §§493.1461 and 1462):

  • Be qualified as a laboratory director or technical supervisor
  • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine licensed to practice medicine, osteopathy, or podiatry in the state in which the laboratory is located
  • Have a doctoral, master's, or bachelor's degree in a chemical, physical, biological or clinical laboratory science and 1 year of training or experience in high-complexity testing
  • Have an associate's degree or equivalent in a chemical, physical, biological, or clinical laboratory science and 2 years of training or experience in high-complexity testing
  • Meet the CLIA requirements to be grandfathered in on the basis of training, experience, and employment before 1992

General supervisors of laboratories that perform molecular genetic testing for heritable conditions must fulfill these CLIA qualification requirements for high-complexity testing. Because the CLIA qualification requirements apply to high-complexity testing in general, laboratories that perform molecular genetic testing should ensure that general supervisors have specific training or experience in the high-complexity molecular genetic testing the laboratory performs.

Responsibilities. CLIA requires general supervisors for high-complexity tests to be responsible for day-to-day supervision or oversight of laboratory operations and of the personnel who are performing testing and reporting test results (42 CFR §493.1463). General supervisors of laboratories that perform molecular genetic testing for heritable diseases and conditions must meet the following CLIA responsibility requirements:

  • Be accessible to testing personnel at all times testing is performed
  • Provide day-to-day supervision and direct supervision of all testing personnel, including those who have been grandfathered in
  • Monitor testing procedures to ensure the quality of analytic performance
  • Fulfill the following duties when delegated by the laboratory director or technical supervisor:

--- Ensure that remedial actions are taken when test systems deviate from the established performance specifications.

--- Ensure that patient test results are not reported until all corrective actions have been taken and the test system is properly functioning.

--- Provide orientation for all testing personnel.

--- Annually evaluate and document the performance of all testing personnel.

Testing Personnel Qualifications and Responsibilities

Qualifications. CLIA requires testing personnel who perform high-complexity testing to have at least one of the following sets of qualifications (42 CFR §§493.1489 and 1491):

  • Be a doctor of medicine, doctor of osteopathy, or doctor of podiatric medicine
  • Have an earned doctoral, master's, or bachelor's degree in a chemical, physical, biological or clinical laboratory science or medical technology from an accredited institution
  • Have an earned associate's degree in a laboratory science or medical laboratory technology from an accredited institution
  • Meet the CLIA requirements to be grandfathered in on the basis of training, experience, and employment before 1992

These qualification requirements apply to testing personnel who perform molecular genetic testing for heritable diseases and conditions. Laboratories should ensure that testing personnel have received adequate training, including on-the-job training, and demonstrate competency in high-complexity molecular genetic testing before performing patient testing.

Responsibilities. CLIA requires persons who perform high-complexity testing to follow laboratory procedures and protocols for test performance, quality control, results reporting, documentation, and problem identification and correction (42 CFR §493.1495). Personnel who perform molecular genetic testing for heritable diseases and conditions must meet these requirements.

Personnel Competency Assessment

CLIA requires laboratories to establish and follow written policies and procedures to assess employee competency, and if applicable, consultant competency (42 CFR §493.1235). CLIA requirements for laboratory director responsibilities (42 CFR §493.1445[e][13]) specify that laboratory directors must ensure that policies and procedures are established for monitoring and ensuring the competency of testing personnel and for identifying needs for remedial training or continuing education to improve skills. Technical supervisors are responsible for implementing the personnel competency assessment policies and procedures, including evaluating and ensuring competency of testing personnel (42 CFR §493.1451[b][8]). Laboratories that perform molecular genetic testing for heritable diseases and conditions must meet these general personnel competency assessment requirements. Laboratories also should follow the applicable CMS guidelines to establish and implement policies and procedures specific for assessing and ensuring the competency of all types of laboratory personnel, including technical supervisors, clinical consultants, general supervisors, and testing personnel, in performing duties and responsibilities (96). For example, the performance of testing personnel must be evaluated and documented at least semiannually during the first year a person tests patient specimens. Thereafter, evaluations must be performed at least annually however, if test methodology or instrumentation changes, performance must be re-evaluated to include the use of the new test methodology or instrumentation before testing personnel can report patient test results. Personnel competency assessments should identify training needs and ensure that persons responsible for performance of molecular genetic testing receive regular in-service training and education appropriate for the services performed.

Considerations Before Introducing Molecular Genetic Testing or Offering New Molecular Genetic Tests

Recommendations described in this report should be considered, in addition to appropriate professional guidelines and recommendations, when planning and preparing for the introduction of molecular genetic testing or offering new molecular genetic tests. The following scenarios should be considered during the planning stage:

  • Introducing a new molecular genetic test that has not been offered in any laboratory
  • Introducing a genetic test that previously has been referred to another laboratory but will be performed in-house
  • Introducing an additional genetic test that can complement a molecular genetic test that has been performed for patient testing

These scenarios present different planning concerns, including needs and requirements for training and competency of laboratory personnel, laboratory facilities and equipment, selection of test methods, development of procedure manuals, establishment or verification of performance specifications, and personnel responsibilities. In addition, the following factors should be assessed:

  • Needs and demands of the new test, which can be assessed by consulting with ordering physicians and other potential users of laboratory services and by conducting other market analyses
  • Intellectual property or licensing concerns that might result in restricted use, increased costs, or both of certain genetic tests

Quality Management System Approach for Molecular Genetic Testing

The quality management system (QMS) approach provides a framework for managing and monitoring activities to address quality standards and achieve organizational goals, with a focus on user needs (41,109). QMS has been the basis for many international quality standards, such as the International Organization for Standardization (ISO) standards ISO 15189, ISO 17025, and ISO 9001 (91,139,140). These international QMS standards overlap with certain CLIA requirements but are distinct from CLIA regulations.

Because QMS is not yet a widely adopted approach in the United States, laboratories that perform molecular genetic testing might not be familiar with QMS implementation in current practice. The QMS approach has been described in several CLSI guidelines (41,109). New York state CLEP and CAP have included QMS concepts in the general laboratory standards (15,102), and CAP and the American Association for Laboratory Accreditation have begun to provide laboratory accreditation to ISO 15189 (141,142). Laboratories that perform molecular genetic testing should monitor QMS development, because implementing the QMS approach could help laboratories accept international test referrals and improve quality management of testing.

Conclusion

The recommendations in this report are intended to serve as guidelines for considering and implementing good laboratory practices to 1) improve quality and health-care outcomes related to molecular genetic testing for heritable diseases and conditions and 2) enhance oversight and quality assurance practices for molecular genetic testing under the CLIA regulatory framework. The report can be adapted for use in different settings where molecular genetic testing is conducted or evaluated. Continual monitoring of the practice and test performance of molecular genetic tests is needed to evaluate the effectiveness of these recommendations and to develop additional guidelines for good laboratory practices for genetic testing, which will ultimately improve public health.

Acknowledgments

This report is based, in part, on contributions by Judith Yost, MA, Penny Keller, Ronalda Leneau, MS, Penny Meyers, MA, Division of Laboratory Services, Centers for Medicare & Medicaid Services Steven L. Gutman, MD, Elizabeth Mansfield, PhD, Office of in Vitro Diagnostic Device Evaluation and Safety, Food and Drug Administration and Sharon E. Granade, MPH, Emily S. Reese, MPH, Andrea Scott Murphy, Howard E. Thompson, and Pamela J. Thompson, MS, Division of Laboratory Systems, National Center for Preparedness, Detection, and Control of Infectious Diseases, CDC.

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Clinical Laboratory Improvement Advisory Committee Genetic Testing Good Laboratory Practices Workgroup

Chairperson: Carol L. Greene, MD, University of Maryland School of Medicine, Baltimore, Maryland.

Members: Michele Caggana, ScD, New York State Department of Health, Albany, New York Tina Cowan, PhD, Stanford University Medical Center, Stanford, California Andrea Ferreia-Gonzalez, PhD, Virginia Commonwealth University, Richmond, Virginia Timothy O'Leary, MD, PhD, Department of Veterans Affairs, Silver Spring, MD Victoria M. Pratt, PhD, Quest Diagnostics Nichols Institute, Chantilly, Virginia Carolyn Sue Richards, PhD, Oregon Health Sciences University, Portland, Oregon Lawrence Silverman, PhD, University of Virginia Health Systems, Charlottesville, Virginia Thomas Williams, MD, Methodist Hospital, Omaha, Nebraska Jean Amos Wilson, PhD, Laboratory Operations, Berkeley HeartLab, Inc., Alameda, California (formerly Genetics Services Laboratory, Sequenom, Inc) Gail H. Vance, MD, Indiana University School of Medicine, Indianapolis, Indiana Emily S. Winn-Deen, PhD, Cepheid, Sunnyvale, California.

Clinical Laboratory Improvement Advisory Committee (2007--2008)

Chairpersons: Lou F. Turner, DrPH, North Carolina State Division of Public Health, Raleigh, North Carolina (September 2005--February 2008) Elissa Passiment, EdM, American Society for Clinical Laboratory Science, Bethesda, Maryland (September 2008--Present).

Members: Ellen Jo Baron, PhD, Stanford University Medical Center, Palo Alto, California Christine L. Bean, PhD, New Hampshire Department of Health and Human Services, Concord, New Hampshire Susan A. Cohen, Bethesda, Maryland Joeline D. Davidson, MBA, West Georgia Health System (Retired), LaGrange, Georgia Nancy C. Elder, MD, University of Cincinnati, Cincinnati, Ohio Merilyn D. Francis, MPP, The MITRE Corporation, McLean, Virginia Julie A. Gayken, HealthPartners and Regions Hospital, Bloomington, Minnesota Carol L. Green, MD, University of Maryland School of Medicine, Baltimore, Maryland Geraldine Susan Hall, PhD, Cleveland Clinic Foundation, Cleveland, Ohio Norman Ross Harbaugh, MD, Atlanta, Georgia Lee H. Hilborne, MD, UCLA School of Medicine, Los Angeles, California Kevin Mills McNeill, MD, PhD, State Epidemiologist, Mississippi Department of Health, Jackson, Mississippi Dina R. Mody, MD, The Methodist Hospital, Houston, Weill Medical College of Cornell University, Houston, Texas James Harold Nichols, PhD, Baystate Medical Center, Springfield, Massachusetts Gary Don Overturf, MD, University of New Mexico School of Medicine, Albuquerque, New Mexico Stephen Raab, MD, University of Colorado Denver, Aurora, Colorado Linda M. Sandhaus, MD, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio Jared N. Schwartz, MD, PhD, Presbyterian Healthcare, Charlotte, North Carolina David L. Smalley, PhD, Tennessee Department of Health, Nashville, Tennessee Thomas Williams, MD, Methodist Hospital, Omaha, Nebraska Emily S. Winn-Deen, PhD, Cepheid, Sunnyvale, California Rosemary E. Zuna, MD, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Designated Federal Official: Thomas L. Hearn, PhD, National Center for Preparedness, Detection, and Control of Infectious Diseases, CDC, Atlanta, Georgia.

Ex-Officio Members: Steven L. Gutman, MD, Food and Drug Administration, Rockville, Maryland Judith Yost, MA, Division Laboratory Services, Centers for Medicare & Medicaid Services, Baltimore, Maryland Devery Howerton, PhD, National Center for Preparedness, Detection, and Control of Infectious Diseases, CDC, Atlanta, Georgia.

Liaison Representative: Luann Ochs, MS, Becton-Dickinson Diagnostics---TriPath, Durham, North Carolina.


New Genome Test Shows A Child’s Risk Of Disease — Before They’re Born

What if we could predict the genetic risks of children before they were born and find ways to mitigate these risks before conception? Orchid, a company that helps couples have healthy babies by offering a new type of genetic test, is making it possible to quantify risks for couples who are planning to have a child in the future.

Today, Orchid announced a $4.5 million seed funding round and backing from top institutional venture capitalists and founders of established companies, including 23andMe. Orchid has created the first test on the market to examine the whole genome of both partners and evaluate the genetic risk of their child having common chronic diseases. Orchid also provides physician oversight and expert support to couples, including a personalized consultation with a board-certified genetic counselor.

Testing for Genetic Risks

Orchid's Couple Report is a saliva-based genetic test that couples can take at home to determine if their future child would have a higher risk of certain genetic diseases. The test analyzes both partners' DNA and looks for 10 diseases: breast cancer, prostate cancer, heart disease, atrial fibrillation, stroke, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, schizophrenia, and Alzheimer's disease.

"We are able to determine how likely these 10 diseases are to impact the health of the couple's future child," says founder and CEO of Orchid, Noor Siddiqui. "In contrast to other genetic tests, which typically only analyze about 2% of your DNA with a genotyping chip, we analyze the entire genome. We do 100% and look at all 3 billion bases."

By evaluating the whole genome of both partners, the company can combine the results to determine their future child's risk profile and send couples the results of the test in four to six weeks. Couples receive three reports: a couples report, an individual report for the female partner, and an individual report for the male partner.

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"We model how both partners' DNA are going to recombine in their future child so that we can give them a risk estimate," says Siddiqui. Couples can already sign up for Orchid's waitlist to get early access to the Couple Report.

Understanding Complex Genetic Conditions

Orchid's products including a couples report showing parents their future child's potential risks of . [+] disease

Traditional genetic testing that is still used today is carrier screening for recessive traits. It helps determine if a person is a carrier of a recessive genetic disease. Usually, they test the female partner first. If the female is a carrier, then they screen the male partner for rare variants.

What makes Orchid different is its test can check for complex diseases and not just recessive conditions. Genetics is complex because there is more than one gene that causes the disease. There are millions of variants that contribute to the risk of major diseases, such as heart disease or schizophrenia.

"The main advance that has happened in genomics in recent years is that now we can finally measure genetic susceptibility for diseases that have a more complex architecture, which means there are millions of variants that are collectively involved in determining how low or high risk that individual is for developing a disease," says Siddiqui.

Since every report from Orchid comes with a personalized consultation with a board-certified genetic counselor, couples can create an action plan. Options include IVF and embryo screening, and Orchid is planning to offer couples embryo health reports later this year that will analyze 100% of each embryo's genome and check for genetic risks.

"I grew up like millions of other Americans with family members that had devastating diseases," says Siddiqui. "It felt really unfair that one family member had to suffer while others did not. I was compelled by the idea of understanding why some people win the genetic lottery at birth and are healthy."

Preventing chronic conditions in future generations by evaluating risk factors is Orchid's goal. The prevention of diseases through embryo screening and IVF is already widely accepted. For example, the American Society for Reproductive Medicine (ASRM) supports the rights of patients to make informed choices about their child's future.

Knowing if you or your future children have an elevated genetic risk for diseases creates personal power. You can monitor your biometrics, get earlier screenings and make lifestyle changes. It allows you to be proactive about your health and advocate better for yourself by going to the doctor. You can also choose to have IVF and embryo screening for your future child. Understanding your personalized genetic data gives you options.

Thank you to Lana Bandoim for additional research and reporting in this article. I’m the founder of SynBioBeta, and some of the companies that I write about are sponsors of the SynBioBeta conference and weekly digest.


For more information about genetic ancestry testing:

The University of Utah provides video tutorials on molecular genealogy.

The International Society of Genetic Genealogy promotes the use of DNA testing in genealogy.

The National Human Genome Research Institute discusses human origins and ancestry.

GeneReviews: Resources for Genetics Professionals--Direct-to-Consumer Genetic Testing

The Tech Museum of Innovation provides information about how ancestry testing works.

The Smithsonian National Museum of Natural History's exhibit 'Genome: Unlocking Life's Code' discusses genetic ancestry testing. The exhibit also discusses the African Diaspora and its influence on heredity and genealogy.


Introduction to Genetic Testing

Image courtesy of the Human Genome Research Institute

Genetic testing is the process by which a person’s DNA or chromosomes are analyzed for the presence of particular DNA sequences that encode for traits of interest. Most often, genetic testing is used to detect inherited disease causing genes and/or disease-causing mutations that may have arisen spontaneously over time. However, some companies are now offering genetic testing directly to individuals these tests consider everything from ear wax (wet or dry) to ancestry. Additionally, individuals may seek genetic testing before starting a family to determine their carrier status for certain heritable diseases, like cystic fibrosis.

Genetic testing is performed by first taking a blood or saliva sample from a patient. The DNA is then isolated from the cells in the sample. The subsequent analysis performed depends on the goal of the test but often includes DNA sequencing, direct observation of chromosomes, or specialized tests called “microarrays” that are used to detect common mutations present in certain conditions, like breast cancer. Protein levels or protein function can also be used as an indirect measurement of gene function. The results of genetic testing are typically delivered to the patient by a genetic counselor or physician, who will then discuss various preventative measures or treatment options.

Common diseases that are screened for through the use of genetic testing include breast cancer, Huntington’s disease, Fragile X Syndrome, and Tay-Sach’s disease. Genetic testing may also be used for prenatal diagnosis, most frequently to detect abnormalities in chromosome number. Humans have 46 chromosomes, and a deviation in the total chromosome number is referred to as an aneuploidy. One common aneuploidy involves an extra copy of chromosome 21, which leads to the development of Down’s syndrome.

The Genetic Testing Registry (GTR) is a resource provided by the NIH for individuals wishing to learn more about a specific genetic test. According to their website, the information reported for each genetic test includes:

…the test’s purpose, methodology, validity, evidence of the test’s usefulness, and laboratory contacts and credentials. The overarching goal of the GTR is to advance the public health and research into the genetic basis of health and disease.

CLICK HERE to learn more about genetic counselors and their role in interpreting the results of genetic testing