Genome Sequencing for Healthy Individuals? Think Big and Act Small!

In a 2013 blog post, we asked the question: “When should we all have our genomes sequenced?”

At that time, we concluded that the time is not right and that “if we want to use whole genome sequencing in the course of regular preventive care and health promotion, research should be conducted to evaluate its benefits, harms and added value to what we are currently doing.”

A lot has happened since 2013. Several global initiatives have invested heavily in precision medicine projects, featuring, among other things, genome sequencing of individuals in the population or health systems. Examples of such initiatives in the United States include All of Us precision medicine initiative, Cancer Moonshot, and Million Veterans Program. Several health care systems, such as Kaiser Permanente in Northern California, and Geisinger Health System in Pennsylvania are currently collecting, and making use of genomic and other types of data from populations in their system catchment areas. The United Kingdom’s National Health Service has the 100,000 Genomes Project, a bold multi-year initiative to transform U.K. biomedical research and clinical care. It seems likely that these programs will lead to new insights into the genetic underpinnings of disease pathogenesis as well as patient and population health management.

So what is the state of clinical practice in 2017? The Journal of American Medical Association recently launched a new insights series on “Genomics and Precision Health,” consisting of brief educational articles to help nongeneticist clinicians overcome knowledge barriers related to genomics and gain a better understanding about its clinical applications. In the first article of the series, Dr James Evans and his colleagues discuss whether or not routine genome sequencing of healthy individuals can lead to the discovery of clinically relevant and actionable information. While current technology allows us to sequence the entire human genome, doing so for healthy people currently has no clear health benefit. The authors state, “Simply because it is possible to sequence entire human genomes does not mean its broad application in the healthy is a good idea – at least not yet.”

Sequencing human genome is a hugely multiplexed assay yielding millions of genetic variants. It is critical that those thought to be potentially important to health be interpreted for their relevance to disease in the context of other information, including disease status and other nongenetic factors such as diet and medication use. In spite of our recent efforts in research and curation (e.g. ClinGen initiative), our current understanding of the vast majority of genetic variation in humans remains severely limited. Exome or whole genome sequencing of healthy people is not consistent with a fundamental tenet of clinical practice and population screening, namely to refrain from acquiring uninterpretable or potentially misleading information.

In the meantime, Evans et al, suggest that we “think smaller,” proposing a rigorous scientific evaluation of targeted genome sequencing of healthy adults instead of whole genome sequencing. In fact, about 1-2% of the U.S. population carries genetic mutations with high risk of preventable common conditions such as cancer and heart disease. We have written about some of these conditions before, notably familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome, which collectively affect more than two million people in the United States. Recent studies (see examples, here and here) have shown that these conditions are more common than previously thought and may not be adequately ascertained by healthcare providers. Thus, many affected people and at risk relatives are not undergoing recommended interventions that can prevent early deaths from cancer or heart disease.

In January 2017, CDC held a special workshop to discuss targeted genome sequencing of healthy individuals beyond the newborn period, and the importance of public health-healthcare partnerships to explore models of evaluation and implementation. Such an exploration is currently occurring under the auspices of the National Academies “Genomics and Population Health Action Collaborative.” The Collaborative is an ad hoc activity of the Roundtable on Genomics and Precision Health and currently convenes more than 40 key stakeholders with an interest in and commitment to integrating genomics in existing population health programs for health improvement. A Population Screening Working Group led by Dr. James Evans and Mike Murray from Geisinger Health System is designing a framework that will provide the rationale and corresponding evidence for the implementation of large-scale genomic sequencing programs in healthy adult populations. The group will address selection of genes, analytic challenges, return of positive and negative results to participants, workforce and educational needs, and economic considerations. The group will explore current evidence gaps in order to identify important unanswered research questions in this space.

Moving forward, it is imperative that we collect clinical and population data to assess the utility of genome sequencing in healthy individuals, and explore ethical, policy and infrastructure issues related to responsible adoption of this powerful technology. In 2017, we should think big but act small, using the best evidence currently available.

As always, we appreciate the comments and input of our readers.