Equitable Implementation of Cascade Testing for Genetic Disorders: Where are We?

Testing relatives of individuals with genetic disorders, a process known as cascade testing or cascade screening, is critical for identifying those needing health services that can prevent morbidity and mortality. Yet, cascade testing is poorly implemented in clinical practice. For example, there are several genetic conditions with CDC tier 1 evidence-based recommendations for cascade testing, such as hereditary breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia. Collectively, these conditions alone affect about 3 million people in the United States alone, yet only a small proportion of relatives benefit from cascade testing. Clinical and public health methods and strategies are needed for communicating disease risk to family members and providing equitable access to cascade testing in all segments of the population, including racial and ethnic minority groups, rural communities, and people with lower incomes.

A 2018 scoping review, along with a systematic review from 2020, described barriers and facilitators, cost-effectiveness and policy interventions related to cascade testing. The review articles identified several gaps in implementation of cascade testing and areas for future research. These include suboptimal communication between the proband and family and geographic barriers to obtaining genetic services. Few US studies examined interventions for cascade screening or used rigorous study designs such as randomized controlled trials. The articles identified a need to conduct rigorous intervention studies on cascade screening in diverse US populations and assessing the impact of state policies.

We present here a quick update of cascade testing articles from PubMed from 2018 through January 11, 2022. We identified a total of 107 new publications related to cascade testing. These included 59 original research studies, 5 systematic reviews, 9 publications related to guidelines, 1 related to methods, 28 commentaries or non-systematic reviews, and 5 study protocols describing future research. Familial hypercholesterolemia was the most studied individual disease (n=28). Cardiovascular diseases and cancer predisposition syndromes were the focus of 35 and 18 original research studies, respectively. One study addressed maturity-onset diabetes of the young (MODY), one addressed Gaucher disease, and 4 studies focused on cascade testing in general, without any specific condition.

The 59 original research studies were conducted in multiple countries. Sixteen were conducted in US populations, with the remainder studying populations in the UK (n=8), Australia (n=6), Spain and Brazil (n=4 in each), Canada, the Netherlands, and Estonia (n=2 each) and single studies in multiple countries.

The 2018 scoping study identified two items that have yet to be addressed in the literature. One is the need to increase the number of US studies focusing on national and/or state policy recommendations, and another is utilization of rigorous study designs. None of the US-based studies we reviewed addressed policy recommendations, and none used a randomized control trial study design. However, the authors of one study protocol publication indicated they will provide important legal and policy information regarding contacting relatives and another study protocol publication proposes a randomized control study.

Diversity of study populations was another topic area identified as needing additional research in the 2018 scoping review. Of the 15 US-based studies published since the scoping review, one identified access to cascade testing for family members as a key challenge in hereditary cancer panel (HCP) testing in the Latino population. The main challenge to access was related to the fact that family members lived outside the US. The challenge of family members living within the US but not near testing centers was also reported. Participants reported the need for educating providers who service Latinos and other underserved communities about HCP test ordering. In addition to residency location, participants reported that having undocumented immigrant status for family members living outside the San Francisco Bay Area was noted as a challenge to accessing testing.

The 2018 scoping review also called for aligning implementation outcomes within the US original studies, with the Exploration, Adoption/Preparation, Implementation, Sustainment framework (EPIS). We find that the majority of studies focused on outcomes in the exploration phase (n=10; 7 acceptability, 2 feasibility and 1 appropriateness), with a few studies using modeling around cost effectiveness that fell into the preparation phase (n=2). None of the studies reported outcomes within the implementation or sustainability phases of the EPIS model. Four studies addressed pre-implementation barriers and facilitators. Table 1 summarizes the 16 US-based studies and the translational focus of each (i.e., pre-implementation barriers and facilitators or implementation outcomes aligned with EPIS phases).

Another research area suggested in the 2018 scoping review is the need to address geographic and communication barriers to access. One study explored the acceptability of an online video intervention to facilitate communication with family members, and another study assessed the acceptability of telephone counseling.

To reach the full potential of cascade genetic testing, we must develop a much stronger understanding of which component procedures and practices work best and leverage good practices toward delivering precision public health. Join us February 10, 2022, for a  two-hour, virtual mini-symposium to better understand what works well in cascade testing programs for genetic disorders.

Table 1. US original research studies addressing cascade testing from 2018-2021 with area of translational focus (pre-implementation barriers/facilitators or EPIS)