Whole Genome Sequencing for All? The Quest for Evidence Continues

Posted on by Muin J Khoury, Director, Office of Public Health Genomics, Centers for Disease Control and Prevention

a clinician holdig a stethoscope with DNA on the sideIn 1999, Dr. Francis Collins predicted what the practice of genomic medicine in primary care may look like in 2010. He used a hypothetical patient named John, a 23-year-old man with high serum cholesterol. Based on his father’s history of early onset heart disease, John underwent a battery of genetic tests. He was found to be at increased risk of coronary artery disease, colon cancer, and lung cancer. The following is a personalized hypothetical medical intervention based on John’s genomic profile:

“By 2010, the field of pharmacogenomics has blossomed, and a prophylactic drug regimen based on the knowledge of John’s personal genetic data can be precisely prescribed to reduce his cholesterol level and the risk of coronary artery disease to normal levels. His risk of colon cancer can be addressed by beginning a program of annual colonoscopy at the age of 45, which in his situation is a very cost-effective way to avoid colon cancer. His substantial risk of contracting lung cancer provides the key motivation for him to join a support group of persons at genetically high risk for serious complications of smoking, and he successfully kicks the habit.”

In 2017, this vision of personalized medicine based on genomics is yet to be fulfilled. All the interventions mentioned above still require evidence of clinical utility. However, in 2017, whole genome sequencing has become more reliable, feasible and affordable. The benefits of sequencing are becoming clearer in the evaluation of genetic diseases, undiagnosed conditions, prenatal testing, and precision oncology. Nevertheless, the risks and costs of sequencing in the context of primary care still might outweigh its benefits for generally healthy persons, such as John’s hypothetical scenario.

The CDC Office of Public Health Genomics and others have adopted a cautious approach to the use of whole genome sequencing in generally healthy adults or in the context of general medical practice (see previous blogs here and here). We have called for more data on clinical utility to assess the balance of benefits and harms of widespread use of genome sequencing in the general populations.

In 2017, we are beginning to see an evidence-based process to evaluate the clinical utility of genome-based medicine. Vassey et al, published the first of its kind study, a small pilot randomized clinical trial looking at the effect of adding whole-genome sequencing (WGS) to a standardized family history (FH) assessment in primary care. Their goals were to determine whether physicians can manage genomic information appropriately and to evaluate whether genome sequencing findings can facilitate disease detection and prevention and assess adverse effects such as anxiety or increased health care costs.

One hundred patients were randomly assigned to receive a family history report (FH group, 50 patients) or in combination with a WGS report (FH + WGS group, 50 patients), which included monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic traits, and polygenic risk estimates for common disease traits. The authors found previously unsuspected genetic disease results in more than 20% of patients (11/50). All 50 patients carried at least one genetic variant associated with a recessive genetic disease, and 96% carried a pharmacogenomic variant predicting a nonstandard response to one or more medications.

What Vassey et al showed was that genetic variants are frequent, and that primary care physicians were able to manage such findings. Patients tolerated this information well, and many reported making healthy behavior changes within six months. Nevertheless, health care use and associated costs increased in patients with new genetic findings. Whether this increased use will truly improve patient outcomes is unclear from this study.

The authors readily acknowledged the limitations of their study including small sample size and lack of economic and ethnic diversity, and were first to point out that “adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Non-geneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value.”

Understandably, the reactions to the study were mixed with varying levels of enthusiasm and disappointment reflected in headlines of popular press and online media. Sample headlines include:

In many ways, the headlines do not capture the most important point. This pilot study was not designed to answer definitively the crucial question of whether or not whole genome sequencing will be useful in primary care settings, but to begin a longer journey of a systematic scientific approach to address the question. The strengths of the study include its randomized design, use of validated instruments, and use of electronic health records data to assess medical care. Larger trials and more diversity in patient populations will be needed to determine the effect of WGS as a screening tool on the health of populations. Interestingly, a decade ago, our office conducted a much larger randomized clinical trial to evaluate the health benefits of systematic collection and use of family history compared to standard of care and found some health benefits for using family history. Vassey’s study, however, uses family history as the placebo group!

Ultimately, the current study shows that “another barrier to using WGS data in clinical care has begun to fall. The last major obstacle, lack of evidence of utility, will be one of the hardest to overcome, but this pilot study has provided valuable reassurances and useful tools for taking that next step in the sequence of implementing WGS in clinical care.” So the quest for evidence for WGS will continue in the near future even as we debate whether or not WGS is needed in primary care, or it may be more advisable to sequence a more limited set of genes with high disease risk and evidence-based recommendations to reduce these risks.

As always, we welcome the input and feedback of our readers here.

Posted on by Muin J Khoury, Director, Office of Public Health Genomics, Centers for Disease Control and PreventionTags

3 comments on “Whole Genome Sequencing for All? The Quest for Evidence Continues”

Comments listed below are posted by individuals not associated with CDC, unless otherwise stated. These comments do not represent the official views of CDC, and CDC does not guarantee that any information posted by individuals on this site is correct, and disclaims any liability for any loss or damage resulting from reliance on any such information. Read more about our comment policy ».

    Our understanding of the human genome, I sense, is more akin to how much we now know about the universe and less of, as we once thought, a straightforward exercise in reading a conventional map. The observable universe makes up to less than 5% of the entire universe. Conversely, the parts that are hidden from us at this time: roughly 68% of the universe is dark energy, and dark matter makes up about 27%. So, the parts – the majority parts – of the universe that we don’t see are more likely the keys in understanding what really make the universe tick.
    In comparison, the identifiable protein-coding portions – what we traditionally think as the functional parts of a gene – make up only to less than 3% of the whole genome. The remaining parts, the so called “junk”, “non-protein coding”, “selfish” DNA, or, I would name, the “dark DNA” portions make up the majority of the total sequence, 96% plus of the entire genome. In that light, epigenetics might hold the keys to genomic medicine, and, given the complexity of gene-environment interaction, we still have to learn more before fully using the genome in clinical application.

    Human Genome is made up of about 3 billions of the letters Like As, Cs, Gs and Ts that actually makes the organism’s DNA. But Transparency is still there doctors are putting their best efforts to reach the actual resolution. It is not as simple as possible.Well, Thanks for sharing such a nice and informative article.

    It’s interesting to know that a study in 2017 showed that whole genome sequencing allowed physicians to manage disease detection findings and prevention. We’re studying this topic next week in one of my classes, which is why I’m doing prior research to be prepared. Your article is such a big help to me, and I just want to say thank you for helping me understand more about whole genome sequencing solutions. I’ll try to do more research later since I’d like to know how this process is used in today’s modern times. Thanks!

Comments are closed.

Post a Comment

Page last reviewed: April 9, 2024
Page last updated: April 9, 2024