Dr. Bill Gibson (biography and disclosure)
What I did before
To be honest, Direct-to-Consumer Genetic Testing (“DTC” Genetic Testing) wasn’t really on my radar until a patient showed up on my doorstep with a result in hand. Broadly speaking, I used to see three main applications for sequencing a large number of genes in a specific individual. The first application was for ancestral origin: looking at DNA sequences all over the genome to get a better idea of a specific person’s ancestry. Because different bits of the genome map track back to different regions of the world map, we can get a rough idea of where someone’s historic (and sometimes prehistoric) relatives used to live. Medical applications of this approach seem pretty limited, so some genomicists call it “recreational genomics.” It doesn’t really require full sequencing of the human genome, but many private sequencing providers offer it. The second application is diagnostic: to find rare mutations that have a large effect on someone’s health. These rare mutations truly cause disease. Examples include connective tissue mutations (heart disease), mutations in muscle proteins (muscular dystrophy), certain cancers (e.g. breast cancer, ovarian cancer and colon cancer), mutations in deafness genes and mutations in brain-, eye- and nerve proteins (neurological disease and/or vision loss). These types of rare diseases are often caused by one or two major mutations in a gene, leading to dominant or recessive inheritance. For some of them, any one among a large group of genes could harbour mutations, so a “one gene at a time” search becomes really long and expensive. In these situations, high-throughput sequencing can be a cost-effective way to get almost all of the genes in one go, letting us quickly find the type of mutation(s) we are looking for. The third application was semi-predictive: to find common genes that have a small effect on someone’s health, but that may have a large effect on health when added (or multiplied) together. The hope behind this type of testing is that these sequences can be assembled into a profile that would have some ability to classify a person into “high-risk” or “low-risk” categories for common diseases, such as heart disease and stroke, diabetes, dementia, asthma and so forth.
What changed my practice
I was referred a patient who had paid privately for high-throughput DNA sequencing, and then had her genome interpreted by several specialists in the field. I was asked to decide whether a particular rare mutation explained a number of unusual features in her medical history. These features were consistent with a common disease, though many of her close relatives also had the same disease. Thus, the presence of a dominant gene in the family was another plausible explanation. Like the result of any test I might have ordered myself, the patient’s data might help me to do my job, but it wouldn’t do my job for me. I therefore also looked at her family history, and it became clear that there was no way to be certain that this specific mutation was causing her health problems. We are now trying to get better evidence to match the gene with the disease by testing other family members for the same mutation found by the private genome sequencing company. We are not sequencing all of their genes, just the one area where the mutation is found. We can do this because we have a research lab, but this is beyond the scope of what many family docs could do in the clinic.
This case made me more skeptical about the current medical usefulness of DTC genetic testing for common diseases, whether it finds rare mutations or common variants. That third application now seems to be much more distant in the future.
What I do now
From the perspective of one’s own ancestry, DTC genetic tests can return data that is interesting, and sometimes surprising, but it is difficult to imagine a good rationale for changing medical management on the basis of ancestry. It must be remembered that the “family history” one learns from ancestry testing is not the same as the traditional “family history” that a family doc would collect as part of routine care.
From a medical perspective, I advise people who are thinking about DTC genetic testing to think of it like the over-the-counter (OTC) medical tests available in many pharmacies. An OTC pregnancy test is designed to answer a focused question: whether or not a woman is pregnant. An OTC cholesterol test answers a similarly focused question. I tell people that DTC genetic tests very rarely return results that are medically actionable, unless originally done to answer a focused question about a rare genetic disease.
That said, most DTC genetic testing is still not well suited to detecting rare disease-causing mutations. Patients who have concerns about a specific genetic disease, or an unusual problem that may be genetic in nature, are best served by a referral to the Provincial Medical Genetics Program or to the BC Cancer Agency’s Hereditary Cancer Program. Though DTC genetic testing may uncover major mutations that cause cancer or other diseases, current methods “flag” a large number of rare DNA changes that aren’t really there (false positive mutations) and fail to flag an unknown number true mutations – thus generating false negative results. This makes it hard for a practitioner to know if the real mutation he or she is looking for will actually be found the list returned by the company. Targeted testing of specific candidate genes through a certified lab (such as the Molecular Genetics Lab at Children’s and Women’s Health Centre of BC) offers the highest sensitivity and specificity in the context of rare genetic diseases.
Although DTC genetic tests can return a “panel” of common DNA sequences that match up some of the time with common diseases, these “panels” don’t reliably tell you who will get sick, when they will get sick, or how sick they will get. A multi-generation family medical history (three generations if known) remains the gold standard to assess risk for common diseases; DTC genetic testing doesn’t yet do better than that.
Being a Careful Consumer – A Checklist:
Practitioners who are asked by a patient about DTC genetic testing may suggest that the patient consider the following points:
1. What do you really want to find out from the test?
Ancestry tests can be fun and interesting, but should not be confused with tests that yield medically actionable information. If the patient is seeking a definitive diagnosis for a condition such as chronic pain, hormonal problems or other poorly-defined conditions, DTC testing is likely to raise more questions than it answers. If the patient is seeking a definitive diagnosis for a rare genetic condition, this is best pursued through their local Medical Genetics service.
2. How long has the company been doing DTC testing, and how many tests have they done?
There are many players in this field, and it is much easier for a company to generate DNA sequence data than it is to interpret it. Patients should avoid new start-up companies that appear to be cashing in on a trend.
3. Is the testing offered in a lab that abides by CAP- and CLIA-regulations?
Patients may not know what the Clinical Laboratory Improvement Amendments or the College of American Pathologists are, but the lab should! Labs offering testing should comply with one or both of these. Labs outside of North America should have their procedures certified by an appropriate independent body.
4. Is the company doing the test itself, or is it acting as a “broker”?
Some companies collect the DNA and send it off elsewhere for sequencing. A careful consumer or GP should know where the testing is being done, and also what is the real “value added” by the company collecting the sample.
5. Who is actually doing the interpretation of the test?
Any test that is intended to be medically actionable should be signed out of the lab by someone with the legal authority to take responsibility for medical reports – like a pathologist, medical microbiologist, molecular geneticist, and so forth. It should not be a series of fields generated by a computer.
References and Further Reading:
Ashley E et al., “Clinical assessment incorporating a personal genome.” The Lancet, Volume 375, Issue 9725, Pages 1525 – 1535, 1 May 2010
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60452-7/abstract
This group of authors suggest a way to start with population-prevalence data, throw in common DNA variants from whole genome sequencing and calculate an individual’s risk for developing common disease. Their algorithm generates a percentage risk, but the accuracy of this risk assessment (e.g. whether or not 10% of people who receive a 10% risk for type 2 diabetes from the calculation will actually go on to get type 2 diabetes) is not yet known.
Useful Websites to find out more:
UBC CPD Webinas:
| Monday Jan 28, 2013 7-8 pm PST | Genomics in Primary Care: What’s Ready for Prime Time? Part A with Dr. Linlea Armstrong and Dr. Bob Bluman | Register |
| Monday March 7, 2013 7-8 pm PST | Genomics in Primary Care: What’s Ready for Prime Time? Part B with Dr. Linlea Armstrong and Dr. Bob Bluman | Register |
BC Clinical Genomics Network
http://www.bccgn.ca
How to Make a Referral to the BC Cancer Agency Hereditary Cancer Program
(Site contains downloadable referral form)
http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/HereditaryCancerProgram/referralinformation/default.htm
How to Make a Referral to the Provincial Medical Genetics Program
(Site contains downloadable referral forms)
http://www.bcwomens.ca/Services/Medical+Genetics/ContactUs.htm
How to Order a Specific Genetic Test from BC’s Molecular Genetic Laboratory
(Site contains interactive test menu and downloadable requisition – please note that this lab does not offer direct-to-consumer genetic testing)
http://www.genebc.ca
Wikipedia
http://en.wikipedia.org/wiki/Genetic_testing#Direct-to-Consumer_genetic_testing
Genetics Home Reference
http://ghr.nlm.nih.gov/handbook/testing/directtoconsumer
American College of Medical Genetics and Genomics Statement on DTC Genetic Testing
http://www.acmg.net/StaticContent/StaticPages/DTC_Statement.pdf
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Still too esoteric a topic to affect my practice but the potential is there several years from now hopefully when I have already retired.
I a totally against DTC genetics as I don’t know what I’m getting into
interesting and well written this makes total sense to me that this is not usually medically actionable
nice article, i think we should be more careful with genetic testing though it makes tantalizing reading since it may turn out more questions than we can attempt to answer.
Interesting article that brings up important guideline principles and insight into DTC genome testing.
interesting information to assist FDr with questions around DTC genome testing
I think it is definite something that will be evolving over time. The application is still limited so we have to use this wisely. The cost is coming back and picking credible company is important.
I am about to retire so will leave this to the next generation
As a radiologist , I had no idea this service was even in existence.
Interesting, but for now will unlikely change my practise
dtc has no place in actionable medical practice for now. 3 generations testing,specific disease and the qualification of the interpreter is important.
dtc offers no actionable medical practice for now. 3 generations testing target a disease and quality of the interpreter is important
Why I, as a patient, was forced to go the Direct to Consumer route:
For 26 years i had been looking for answers here in Canada. I trusted doctors greatly, expecting them to give me the right answer. Unfortunately my trust was shattered as time – and negative experiences happened. I went through many episodes of being given medicines that severely negatively affected my life. At first i could handle many kinds of medicines. But while i was in College an Endocrinologyst gave me a medicine that did great damage to me. Even though within 2 hrs or so of taking that medicine drastic things started happening, 3 doctors (including the Endocrinologyst) persuaded me that my symptoms were not in the pharmaceutical info, that i had to take it 6 months in order to see positive results. During that time people at the College, at Church etc. were noticing drastic negative changes in me. A few years later, when i was trying to make sense of what had happened, i found out that the medical side effect info in the pharmaceutical book was based on males taking that medicine. No info had been available for females. The doctors were making decisions about me based on that info. The more time went, the more i noticed that medicines i could easily handle before taking that medicine, i could no longer tolerate. It was through much time and taking much medicines that i came to see this.
There were times i bled much (for a month and a half etc.) and a doctor told me to stop a medicine. I never was checked for any bleeding disorders. There were times when hormone reacted severely to me. Horrible things happened. No doctor knew the answers why. Through time i was sent to many specialists, tried many, many types of medicines. Side effects such as hand eye coordination problems, vision problems, muscle spasms, blood pressure going way over 200 systolic and even to 149 diastolic, etc. etc. happened.
Things were getting so desperate that i took course like Health Psych, Bio Psych etc. to navigate this medical crisis better. I am very thankful that i did, because i learned how to research, how to better navigate the doctor patient relationship, in these hard situations etc.
I was made aware that American medical research was much more advanced than the Canadian system re. my own health areas.
There were times i even came to the point of wanting to end my life because of this whole frustrating experience. I desperately wanted answers/medicines that were helping my body, but no answers were coming. Also, at this time many members of my family were going through similar situations. They were in a worse situation because their GP was not sending them to appropriate medical specialists.
Through a friend i came in touch with a GP who had opted out of the medical system and practicing alternative medicine. He initially sent my blood to US for a genetic test re. liver. Results of that test showed that i did not have enzyme to break some of that medicine i had been given. My own doctors here in Canada did not pay much attention (because it was a direct to consumer test). That was in 2008. If they had paid attention, it would have given answers in one area.
More time went, and my health was now severely going downhill. I went to a doctor who told me that all of my reactions (and even my liver being enlarged, hormone depletion,etc.) was psycho somatic. I told him that i was going to prove him wrong. That is when i researched and found something called Exome genetic test available in the US.
What are the positives that have happened since taking that test? 1) One genetic place found out that we are carriers of hemophelia. This is helping one of my sisters who had a bleeding problem since she was a teen. Because of where she was bleeding, her GP never sent her to the blood specialist. It has been years where she was given various medicines for peripheral symptoms and had severe reactions, but not deal with the cause. Now she will get the proper diagnosis.
2) That test i took in 2008 was confirmed by the Exome. I could have had better answers in 2008 if i had been referred to the Provincial medical genetic program or some other place. I NEVER COULD HAVE GOT TO ANY GENETIC PROGRAM in Canada because no doctor recognized that there was anything of that nature going on. And no Specialist ever mentioned any Provincial Genetic Program.
3)Now there is the possibility of my whole family getting help. Before no doctor was really hearing any of my family members…..even though we were mentioning the same kind of symptoms, the same kind of side effects etc. Some of my family members had the same GP. I did not. But i did convey information about my family to the doctors. FINALLY our situation is taken a look at.
4) Some of my family members are at precarious health situations. There was no hope whatsoever before. Now there is some hope – esp. because of everyone’s situation being studied by one team of genetic investigators.
5) My GP, medical specialists, etc are finally taking our family situation seriously. We are getting better medical care. No longer are we being disbelieved cos there is more evidence through that Exome (diagnostic) that we are having medical situations that our doctors had not looked at before.
The way the Canadian medical system is (with its horrendous shortcomings when it comes to diagnosing and treating unusual medical situations), there is ample need for Direct To Consumer genetic testing.
Even if per chance no medical answers come to me at this time ie. 2013 (given that genetic testing is much faster than the ability to get meaningful/necessary analysis), i still would have been somewhat happy knowing that i participated in cutting edge science, and that i donated my DNA for research. At least i did not decide to end my life (because of the unbearable nature of my health); instead i did something to get answers. And in the process i triggered more discussion about this topic in the medical community.
How best to check for Leber’s hereditary optic neuropathy?