Evaluating Outcomes of Genomic Screening

Familial hypercholesterolemia (FH) is a relatively prevalent genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C), with associated risk for premature cardiovascular events.Effective lipid-lowering therapies are available; however, FH is underdiagnosed, representing missed opportunities for early intervention.In this randomized clinical trial (RCT), Vassy and colleagues 1 examined the effect of opportunistic genomic screening for FH on LDL-C levels. 1 Participants with suspected pathogenic or likely pathogenic variants related to FH were ascertained through the Million Veteran Program research biobank and enrolled in the trial. 1 Trial participants were randomized to result disclosure at baseline (immediate results group) or after 6 months (delayed results group). 1 Following clinical confirmation, genetic results were disclosed via telegenetic counseling. 1 At 6 months, while not statistically significant, a greater reduction in LDL-C levels (-10.5 [95% CI, -21.9 to 1.0] mg/dL; P = .07)and intensified treatment (11 of 55 participants (20.0%) vs 5 of 57 participants (8.8%); P = .09)were observed in the immediate results group compared with the control group. 1 This RCT demonstrates approaches to address several methodological challenges in the evaluation of genomic screening, which may be transferable to subsequent studies.. Clinical genetics has traditionally relied on patient manifestations and family history to identify individuals eligible for genetic testing.However, it is now recognized that current testing algorithms result in underdiagnosis of monogenic disorders. 2Biobank studies have repeatedly shown that genomic screening in unselected populations can increase detection of pathogenic variants related to monogenic disorders compared with indication-based approaches. 2 Genotype-first identification of pathogenic variants related to monogenic disorders can have implications for early detection, prevention, treatment, and cascade testing for relatives. [3]4][5] Notable applications of genomic screening that are currently implemented or under investigation include opportunistic screening for secondary findings from diagnostic exome or genome sequencing, population-based screening for actionable adult-onset conditions (in particular FH, hereditary breast and ovarian cancer, and Lynch syndrome), and the use of genomic sequencing in newborn screening, a more nascent application.Across jurisdictions, the status of genomic screening varies from research studies to pilot studies to clinical implementation.There is also heterogeneity in extent to which genomic screening is reimbursed in public health systems or by insurers.Decisions about reimbursement or clinical adoption of health technologies, including genomic technologies, may consider factors that include clinical validity, clinical effectiveness, cost-effectiveness, ethics, and social values. 6These evaluative frameworks typically use evidence-based medicine hierarchies, where RCTs can provide a high level of evidence 7 ; however, RCTs of genomic screening are scarce.Conducting RCTs and evaluating clinical outcomes in the context of genomic screening, whether opportunistic or population-based, can be challenging.This in turn can pose challenges for decision-making regarding reimbursement and implementation.Genetic test results can have effects on a myriad of outcomes for the patient undergoing testing, family members, and the health system. 8While evidence of improvements in health outcomes, such as morbidity and mortality, would be important for demonstrating the value of genomic screening, one challenge is that, as with any intervention aimed at prevention or screening, there may be a long lag between the intervention and changes in health outcomes. 9Therefore, the use of intermediate outcomes is often necessary. 9Vassy and colleagues 1 demonstrate the use of LDL-C, intermediate outcome in the context of FH.Given the heterogeneity of genetic disorders with +