Genomic Ascertainment - Clinical and Behavioral Aspects

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Predictive genomic medicine or precision genomic medicine is of the highest medical importance and is an active area of research. We began piloting the return of genome-wide rare variants with the inception of the ClinSeq program in 2006, well before exome and genome sequencing became widespread (Biesecker et al., Genome Res 2009). We have continually expanded our work in this area by searching the genome for high penetrance variants that could be useful for clinical care, reproductive risks, pharmacogenetics, and other uses. My vision is that the genome is a health care resource, not a test, and that the cost of this health care resource can be amortized over the lifetime of an individual, long after its primary indicated usage is accomplished. Indeed, it was our work on ClinSeq that undergirded the recommendations we made for secondary findings (opportunistic screening) that were released in 2013 (Green et al., Genet Med 2013) These recommendations were initially highly controversial but with some amendments have now settled into accepted clinical practice an example of how we aim to change the practice of medicine. This paper has been cited more than 1,200 times and has also become the basis of a number of clinical testing laboratories health screening gene sets. ClinSeq has also been a leader in demonstrating to the field that genomes and exomes can be analyzed in healthy people and results returned, with minimal adverse consequences, dispelling the widespread fears about anxiety, depression, health care over-utilization, and other hypothetical risks. ClinSeq was also a charter member of the CSER (Clinical Sequencing Exploratory Research) consortium which allied six research centers to pilot genomics in health care settings. I joined CSER after participating in the study section that evaluated the CSER applications, reasoning that it would be beneficial for ClinSeq and for the other centers to pool efforts and experiences. Genomic medicine has at its foundation prediction predicting phenotype based on genotype. To address this foundational challenge, we need to develop research modes that can model and test the predictive power of genomic variants. Resources such as gnomAD provide critical data on population prevalence but are seriously limited with respect to phenotype data. The UK BioBank is supporting genotype ascertainment, but its data are limited to pre-hoc phenotypes and blood samples and participants cannot be re-contacted. There is thus a compelling need for the capacity to perform bespoke phenotyping based on genotypes. Another major bottleneck in predictive genomic medicine is the return of results. The standard clinical model is for a physician or genetic counselor to meet with a patient for an individual session to describe the results, review the clinical implications, and provide genetic counseling and/or recurrence risks. This is obviously not scalable, and the field is in urgent need of alternative approaches to this challenge the variants from an exome (much less a genome) cannot be returned to a participant with this model. While most presume that this means that exomes and genomes need to be throttled or filtered down to just a single or few clinically relevant variants that can be returned using the standard model, the question should be asked as to whether alternative means to results return can be devised. Our efforts to increase the throughput of return of results lead us to set up a randomized controlled trial comparing standard genetic counselor-provided in person return of results to return of results with a web-based platform. Computerized information provision is much less costly and time-consuming than an in-person counselor if it accomplishes the key goals. Our hypothesis was that the web platform would be non-inferior to the counselor with respect to returning that information. This was tested in an 2x2 design where we separated out the components of the return of results education from actual counseling which is critical since computers cannot counsel. For this experiment we selected carrier testing results, specifically because we were lowering the standard of care (by not providing actual genetic counseling in the web platform arm) and thus felt compelled, from a participant safety perspective, to perform this experiment with genetic test results that were meaningful, but not high impact. We selected carrier results for which there are no known heterozygote phenotypes in order that the educational materials could state that the variant(s) had no health impact for the participants. We showed that the platform was indeed non-inferior in several important outcome measures (See Figure 1 and (Biesecker et al., JAMA Intern Med 2018) Featured Paper #1. We have followed this work with additional analyses showing that there was no significant measurable added value of genetic counseling on top of information provision, either by web or counselor (Lewis et al., Am J Hum Genet 2018), we have also followed up with an analysis of perceptions of uncertainty amongst the recipients of these carrier results, (Umstead et al., Transl Behav Med In Press). In addition, we have undertaken a significant effort to better understand secondary variants in the research setting.