The Consequences of Sequencing Healthy People

The first randomized trial to examine whole-genome sequencing in healthy people uncovers disease-causing genetic variants, but the overall benefits to this population are ambiguous.

By | June 26, 2017


  Physicians are increasingly using patients’ genomic data to fight cancer or diagnose unexplained symptoms. But in individuals with no discernable signs of illness, it’s uncertain whether knowing their genomic blueprints is beneficial, and whether primary care physicians are up to the challenge of managing these data for their patients. In the first study of its kind to evaluate whole genome sequencing in a randomized fashion, published today (June 26) in the Annals of Internal Medicine, researchers report that although primary care physicians are capable of contending with genomic information, its value for healthy patients remains ambiguous.

“It comes down to the question: how many individuals do you wish to scare . . . in order to find that one individual that could be helped?” writes Harvard Medical School biomedical informatics professor Isaac Kohane in an email to The Scientist. He was not involved in the study but has previously collaborated with senior author Robert Green, a geneticist and physician at Harvard Medical School and Brigham and Women’s Hospital. “My own opinion is that if you are in good health, the clinical value is low and the risk is higher than most appreciate.”

Arizona State University law professor and law and genetics expert Gary Marchant holds a different view. In a larger population, “you will find in one or two percent of the people something that is significant and might be actionable. Personally, I think it’s a justification for doing it.” 

See “Should Healthy People Have Their Exomes Sequenced?

Biomedical ethicist and coauthor Amy McGuire, the director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine, says she and her colleagues had questions about whether genome sequencing would cause anxiety or change people’s health care costs or clinical management. So as part of the MedSeq project, the researchers conducted the first study to empirically evaluate the utility of whole genome sequencing in a randomized, healthy population.

The research team recruited nine physicians who, in turn, recruited 10 or so patients each to participate in the study. Out of 100 healthy individuals between the ages of 40 and 65 years, 50 were randomly assigned to have their whole genomes sequenced in addition to receiving a family history report. The other 50 participants received a family history report alone. Physicians received an interpreted report of the patients’ sequencing results, and had to manage their cases.

“We set out to model what the future of genomic medicine might be in a general medicine setting,” says lead author and Harvard Medical School assistant professor Jason Vassy, also a clinician-investigator at Brigham and Women’s Hospital and a primary care physician with Veterans Affairs Boston.

There are numerous genetic variants inaccurately labeled as disease-causing in genetic databases, the authors write in their report. In order to identify legitimate variants predicted to cause disease, patients’ data were painstakingly vetted from an initial list of about 5,000 disease-associated genes and 5 million genetic variants per patient. A clinical laboratory team filtered these down to 200-300 variants, after evaluating whether these genes had been previously reported as pathogenic and whether rarer variants would drastically impair the gene’s protein function. They then whittled this down even further to an average of two to three variants per patient by evaluating whether a variant had sufficient evidence to cause disease and whether the gene itself was associated with a particular disease, among other criteria. Weighing this information “to figure out what is clinically relevant is challenging” and requires a “fair amount of professional opinion,” says clinical genomicist Heidi Rehm, director of the laboratory for Molecular Medicine at Partners Healthcare who led the interpretation of genomes.

“We had two major, surprising findings,” says Vassy. First, his group found variants predictive of rare diseases in 11 out of the 50 patients, a “strikingly high number.” The second surprise was that nine of these patients didn’t show any signs of disease. “They were healthy individuals . . . 50 to 60 years old. In theory, many genetic diseases would have manifest by then.”

Vassy notes that one patient had a variant associated with pituitary disease yet no evidence of a hormone deficiency, and patients with variants associated with heart conditions who went on to have normal cardiac tests.

In the two patients with demonstrable signs of disease—one with a night vision-compromising eye condition called fundus albipunctatus and another with variegate porphyria, a skin condition that produces sunlight sensitivity and reactions to certain medications—now have an explanation for their symptoms. In addition, every sequenced individual had at least one recessive carrier gene linked to a certain condition, notes Marchant, which can be very useful for people planning on having children.

Eight out of these 11 cases were handled appropriately by their managing primary care physicians, as deemed by a panel of genetics experts who reviewed each case. From this small sample of doctors from an elite medical community, who received resources and support, it appears that “that there are ways to educate primary care physicians about whole genome sequencing,” says Yann Joly, research director of the Center of Genomics and Policy at McGill University.  

However, “these conclusions are not well supported,” writes Kohane, as prior studies have shown that for tests that have been around for some time, like the BRCA1, the average primary care doctor and specialist is “neither comfortable nor competent” interpreting these results.

Although sequenced patients did not demonstrate increased psychological distress, they accrued, on average, $350 more in medical expenses than non-sequenced individuals. McGuire stresses “that the follow-up that was done was judged to be clinically appropriate,” and patients could save money in the long run for catching conditions earlier on with such testing.

While researchers found “nothing dramatic in terms of both the benefits and the risks,” Marchant says, life insurance is “one big negative.” Because “life, disability, and long-term care insurance can use this information, [patients] could be affected by or even discriminated against by [their] genetic test results.”

Overall, the lack of disease in the patients with predictive variants highlights a lack of understanding of penetrance—whether a genetic variant will manifest in disease in an individual, stress Vassy and Rehm. According to Vassy, it’s “misleading” to equate advances in big data and genomic tools with similar strides in understanding how genetic variants impact health.

See J.L. Vassy et al., “The impact of whole-genome sequencing on the primary care and outcomes of healthy adult patients,” Annals of Internal Medicine, doi:10.7326/M17-0188, 2017.

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Avatar of: dumbdumb


Posts: 92

June 27, 2017

"Physicians are increasingly using patients’ genomic data to fight cancer or diagnose ...." and "primary care physicians are capable of contending with genomic information"

Those are a good ones! The average physician doesn't have a clue about genomics

June 27, 2017

I havent read the whole paper yet, but from this article, i fail to see the downside. The authors conclude the benefits are ambigious. It seems there is major upside. The potential downside as outlined here are sociopolitical issues that need to be corrected by bolstering GINA.

The other major takeaway is that so-called protective variants or those that mitigate risk variants and explain the penetrance question is underappreciated in genomics. Systems biologists need to come up with a framework to explain how loss of one gene in one pathway can be compensated by another "protective" gene or pathway. 

Avatar of: Interested


Posts: 7

June 28, 2017

However, consider the following study:

“The cumulative results of all persons reporting one or more instances of genetic discrimination showed that 46.2% of individuals at risk for HD experienced some form of unfair treatment. Findings demonstrated a variety of discriminatory experiences classified as falling into the domains of relationships, insurance, employment and transactions (including legal cases and housing rights). Genetic discrimination in the form of insurance was the single most meaningful form of genetic discrimination reported (according to the respondents). These data were gathered between 2005 and 2008, however, just prior to the enactment of GINA in the United States. Canada and Australia have both published concerns about legal protections as well (Lemmens and Miller, 2003; Otlowski, 2007). In addition to discrimination issues, there are issues regarding the sheer complexity of making complaints or seeking redress within the legal system with results revealing a concerning lack of knowledge of formal legal rights, and very poor knowledge of legislation that prevents employers or health insurers from accessing and using their genetic information (Goh et al., in press) (Otlowski et al., 2007; Otlowski, 2007).

In 2015, a life insurance applicant was denied coverage due to a positive BRCA1.  Consider that 1 in 400 women have a BRCA1 or 2 gene which is associated with increased risk.  It does not demand occurrence.  Clinical guidelines given by the U.S. Preventative Services Task Force state that without an associated family history of breast cancer the benefit of initial testing or pursued prevention would be small to zero.  The public is not aware of this guideline.

Recall that GINA covers only health and employment.  It does not cover life insurance, disability or long term care.  And with Trump’s offer to reduce health insurance by 30% if the applicant agrees to a GWAS only opens the door to not only rejected job applications but a feasible lower job placement - all under the guise of corporate policy.  This is a genuine public concern.

All of Us is a service mark of the U.S. Department of Health and Human Services (HHS).  Their position and funding can be altruistic in nature. Notwithstanding, an enforced and enhanced GINA would be necessary to allay public fear of personal information disclosure.

On the other hand, insurance companies are a business entity. Insurance is not a right.  It is a privilege.  It is legitimate that insurance companies need to level the playing field - they have an anthropomorphic intention of surviving.  Remember that the life insurance application asks a myriad of questions and will always request a doctor’s report.  ( And if necessary, a psychiatric report which can be misconstrued if an off label drug is used. ) Therefore, consider that the intention of offering a GWAS from the insurance industry has two conceivable facets:  first, the customer can take the GWAS results and take action on predetermined conditions, and therefore will not use the insurance, or the company will utilize the results to deny coverage, as noted in the annotated study in the previous paragraph.

The public is a non-scientist colleague in this endeavor. The fact is that the results can have limited predictive value, with no guarantee of actionable information, and a misconstrued perception of probabilistic risk can pall the image of an extremely valuable program. The scientific community can understand that multiple linkage possibilities which are either singular in focus or multiple in origin, and considering that > 90% of disease-associated SNPs are located in non-coding regions of the genome, suggests there is no common mechanism for susceptibility to common diseases. This science understands.  Communicating this information to the patient can be difficult considering the somewhat nebulous nature of accurate interpretation of individual data which will be compounded by a certain amount of mistrust. And remember that to assume ignorance in the public is a dangerous and nonproductive precedent.

However, informing the public that when a participant learns that two APOE4 copies will not connote a predisposition to Alzheimer’s if there is a mutation in amyloid B precursor protein gene will prove invaluable for the patient worried about his test results for hereditary Alzheimer’s.  That there is a variant plastin 3 which counteracts SMN1 gene mutation for the autosomal recessive disorder spinal muscular atrophy 1 which can ease a couple’s concern about having a child.  This information should be conveyed to the public as a product of a large statistical database of information of which they can play a part.

As such, the science community needs to appreciate public perception based on expectations and experience.  The public has a certain amount of experience and has an established mistrust when it comes to personal information which will only be exacerbated if information is not treated properly. Therefore, it would behoove the industry to remind the public of potential benefits. The public should be informed that skilled interpretation will guide them through the vast number of variants that may not be biologically relevant to disease or prevention and/or treatment with the discovery of feasible disease.  The ethics of the situation demands persuasion based on above board and transparent informative processes.

This demands that the public receives assurance of non-discrimination and anonymity in health, employment, life, disability and long term care based on GWAS results from All of Us.  This would mean initiation of an enhanced and enforced GINA.    With public participation the potential cohort from all sources would be extremely large. 

However, the insurance industry may understandably deny non-discrimination and anonymity due to the nature of insurance - providing protection against a possible eventuality.  But if this information could be utilized, the cohort and corresponding statistical information would be astounding.

For this reason, obtaining a large database of information must be interpreted as a win-win scenario.  Persuasion should be based on utilitarian ethics.

Insurance industries could obtain GWAS information from applicants with pricing based on current understanding of disease penetrance and treatment. This is not unlike what is done today with doctor’s reports used by underwriters regarding heart disease, diabetes, depression, drug usage, family history and so forth.  Although trained in their job underwriters are not doctors.  Rather than simply denying insurance, payments will be based on what is obtained through the GWAS.  There can be a scaled pricing based on qualified and current genetic information.  It is wise to remember that insurance companies are extremely competitive and interpretation of this information and pricing will refine the system. Change is inevitable with the best acceptance in the form of guidelines which would inherently include a reformed GINA.

The science industry is woefully unprepared for the potential and administrative uses of genetic information based on such studies. Information regarding the genome is expanding exponentially. Not to take advantage of these studies in a focused and goal oriented manner is negligent.  To assume commitment to All of Us, the public must be assured that it follows bioethical guidelines to includes autonomy, beneficence/non-maleficence, legal and informed consent. The insurance industry is a parenthetical participant in obtaining genetic information but a potential and powerful contributor to a common goal of personalized medicine. 

Susan Wolf, a professor of law, medicine, and public policy at the University of Minnesota, told The Scientist that up-front counseling is important. A person needs to understand what they are getting into, she explained. They should be informed, for example, that the US Genetic Information Nondiscrimination Act (GINA) “only covers health insurance and some forms of employment discrimination,” she said. “It’s very rare that there is protection for disability insurance, long-term care insurance, even life insurance.” So if a person’s exome sequence reveals a high risk of, say, Alzheimer’s disease, which may require long-term care, the individual should be aware of the potential risks, she said.

Variants are not necessarily biologically relevant to disease and therefore prognosis or treatment.  Also, heterogeneous complex genetic disorders have multiple linkage possibilities which are either singular in focus or multiple in origin suggesting no common mechanism for susceptibility to common diseases.  Consider that 90% of links are outside the exome.


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