A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia

Ajufo, Ezimamaka; deGoma, Emil M.; Raper, Anna; Yu, Kristen Dilzell; Cuchel, Marina; Rader, Daniel J.

doi:10.1038/s41436-021-01192-z

Cited by 14 publications

(9 citation statements)

References 31 publications

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“…In addition to the potential utility of genetic testing results to inform an individual’s clinical care and outcomes, a positive result has implications for that individual’s family. Studies assessing the uptake of cascade testing among relatives in a diagnostic setting have consistently demonstrated that rates are generally low, though they vary based on clinical area and focus only on just a few genes ( Fehniger et al, 2013 ; Menko et al, 2019 ; Ajufo et al, 2021 ; Lee et al, 2021 ). As population-based and proactive screening methods begin to become more widespread, it is critical to understand how these testing approaches may impact at-risk relatives.…”

Section: Discussionmentioning

confidence: 99%

“…Most studies focusing on genes associated with HCS report cascade testing uptake rates between 30 and 60% ( Fehniger et al, 2013 ; Menko et al, 2019 ; Lee et al, 2021 ). Uptake rates have been much lower (4–12%) among families with FH in the United States ( Ahmad et al, 2016 ; Gidding et al, 2020 ; Ajufo et al, 2021 ), but much higher (30% up to 90%) among families with FH in other Western countries ( Marks et al, 2006 ; Ahmad et al, 2016 ; van den Heuvel et al, 2020 ). Limited data are available on cascade testing uptake for proactive or non-indication-based genetic screening, though results from the Electronic Medical Records and Genomics (eMERGE) phase III study demonstrated that only about one-third of probands who received non-indication-based screening reported sharing their test results with their relatives ( Wynn et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Proband Indication for Genetic Testing on the Uptake of Cascade Testing Among Relatives

et al. 2022

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Although multiple factors can influence the uptake of cascade genetic testing, the impact of proband indication has not been studied. We performed a retrospective, cross-sectional study comparing cascade genetic testing rates among relatives of probands who received either diagnostic germline testing or non-indication-based proactive screening via next-generation sequencing (NGS)-based multigene panels for hereditary cancer syndromes (HCS) and/or familial hypercholesterolemia (FH). The proportion of probands with a medically actionable (positive) finding were calculated based on genes associated with Centers for Disease Control and Prevention (CDC) Tier 1 conditions, HCS genes, and FH genes. Among probands with a positive finding, cascade testing rates and influencing factors were assessed. A total of 270,715 probands were eligible for inclusion in the study (diagnostic n = 254,281,93.9%; proactive n = 16,434, 6.1%). A positive result in a gene associated with a CDC Tier 1 condition was identified in 10,520 diagnostic probands (4.1%) and 337 proactive probands (2.1%), leading to cascade testing among families of 3,305 diagnostic probands (31.4%) and 36 proactive probands (10.7%) (p < 0.0001). A positive result in an HCS gene was returned to 23,272 diagnostic probands (9.4%) and 970 proactive probands (6.1%), leading to cascade testing among families of 6,611 diagnostic probands (28.4%) and 89 proactive probands (9.2%) (p < 0.0001). Cascade testing due to a positive result in an HCS gene was more commonly pursued when the diagnostic proband was White, had a finding in a gene associated with a CDC Tier 1 condition, or had a personal history of cancer, or when the proactive proband was female. A positive result in an FH gene was returned to 1,647 diagnostic probands (25.3%) and 67 proactive probands (0.62%), leading to cascade testing among families of 360 diagnostic probands (21.9%) and 4 proactive probands (6.0%) (p < 0.01). Consistently higher rates of cascade testing among families of diagnostic probands may be due to a perceived urgency because of personal or family history of disease. Due to the proven clinical benefit of cascade testing, further research on obstacles to systematic implementation and uptake of testing for relatives of any proband with a medically actionable variant is warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Impact of Proband Indication for Genetic Testing on the Uptake of Cascade Testing Among Relatives

et al. 2022

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“…Our findings align well with existing research on people's motivations to know about hereditary risks. Three types of reasons for seeking out genetic risk information have previously been described: First, clinical utility and possibility of prevention in the family [19][20][21]. Second, gaining more information to reduce uncertainty and create a sense of control [21,22].…”

Section: More Personalized Information To Allow Informed Decisionsmentioning

confidence: 99%

“…Interventions to support family-mediated disclosure have so far failed to convincingly increase uptake of genetic testing in relatives [17]. Efforts evaluated include motivational interviewing [18], dedicated telephone follow-up [19], offers of genetic testing [20] and online cascade-testing interventions [21]. Although international guidelines have moved towards allowing direct contact in select circumstances [22], healthcare professionals have been reluctant to adopt new proactive practices as legal and ethical regulations remain uncertain and are not easily resolved [23,24].…”

Section: Introductionmentioning

confidence: 99%

A Focus Group Study of Perceptions of Genetic Risk Disclosure in Members of the Public in Sweden: “I’ll Phone the Five Closest Ones, but What Happens to the Other Ten?”

Hawranek

Hajdarević

Rosén

2021

JPM

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This study explores perceptions and preferences on receiving genetic risk information about hereditary cancer risk in members of the Swedish public. We conducted qualitative content analysis of five focus group discussions with participants (n = 18) aged between 24 and 71 years, recruited from various social contexts. Two prominent phenomena surfaced around the interplay between the three stakeholders involved in risk disclosure: the individual, healthcare, and the relative at risk. First, there is a genuine will to share risk information that can benefit others, even if this is difficult and causes discomfort. Second, when the duty to inform becomes overwhelming, compromises are made, such as limiting one’s own responsibility of disclosure or projecting the main responsibility onto another party. In conclusion, our results reveal a discrepancy between public expectations and the actual services offered by clinical genetics. These expectations paired with desire for a more personalized process and shared decision-making highlight a missing link in today’s risk communication and suggest a need for developed clinical routines with stronger healthcare–patient collaboration. Future research needs to investigate the views of genetic professionals on how to address these expectations to co-create a transparent risk disclosure process which can realize the full potential of personalized prevention.

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“…However, the uptake of cascade testing in the United States is low due to a number of barriers, such as the lack of a centralized and coordinated cascade testing program for familial hypercholesterolemia, the inability of health care providers to directly contact family members due to the Health Insurance Portability and Accountability Act Privacy Rule [ 9 ], complex family dynamics, and the burden placed on probands and health care providers in locating and contacting all at-risk family members [ 10 ]. In a recent study [ 11 ], only 28 of 240 (12%) familial hypercholesterolemia probands were able to enroll a family member for cascade testing, which highlights the low uptake of cascade testing in the United States.…”

Section: Introductionmentioning

confidence: 99%

Web-Based Tool (FH Family Share) to Increase Uptake of Cascade Testing for Familial Hypercholesterolemia: Development and Evaluation

Bangash¹,

Makkawy²,

Gundelach³

et al. 2022

JMIR Hum Factors

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Background Familial hypercholesterolemia, a prevalent genetic disorder, remains significantly underdiagnosed in the United States. Cascade testing, wherein individuals diagnosed with familial hypercholesterolemia— probands—contact their family members to inform them of their risk for familial hypercholesterolemia, has low uptake in the United States. Digital tools are needed to facilitate communication between familial hypercholesterolemia probands and their family members and to promote sharing of familial hypercholesterolemia–related risk information. Objective We aimed to create and evaluate a web-based tool designed to enhance familial communication and promote cascade testing for familial hypercholesterolemia. Methods A hybrid type 1 implementation science framework and a user-centered design process were used to develop an interactive web-based tool—FH Family Share—that enables familial hypercholesterolemia probands to communicate information about their familial hypercholesterolemia diagnosis with at-risk relatives. Probands can also use the tool to draw a family pedigree and learn more about familial hypercholesterolemia through education modules and curated knowledge resources. Usability guidelines and standards were taken into account during the design and development of the tool. The initial prototype underwent a cognitive walkthrough, which was followed by usability testing with key stakeholders including genetic counselors and patients with familial hypercholesterolemia. Participants navigated the prototype using the think-aloud technique, and their feedback was used to refine features of the tool. Results Key themes that emerged from the cognitive walkthrough were design, format, navigation, terminology, instructions, and learnability. Expert feedback from the cognitive walkthrough resulted in a rebuild of the web-based tool to align it with institutional standards. Usability testing with genetic counselors and patients with familial hypercholesterolemia provided insights on user experience, satisfaction and interface design and highlighted specific modifications that were made to refine the features of FH Family Share. Genetic counselors and patients with familial hypercholesterolemia suggested inclusion of the following features in the web-based tool: (1) a letter-to-family-member email template, (2) education modules, and (3) knowledge resources. Surveys revealed that 6 of 9 (67%) genetic counselors found information within FH Family Share very easy to find, and 5 of 9 (56%) genetic counselors found information very easy to understand; 5 of 9 (56%) patients found information very easy to find within the website, and 7 of 9 (78%) patients found information very easy to understand. All genetic counselors and patients indicated that FH Family Share was a resource worth returning to. Conclusions FH Family Share facilitates communication between probands and their relatives. Once informed, at-risk family members have the option to seek testing and treatment for familial hypercholesterolemia.

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A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia

Cited by 14 publications

References 31 publications

The Impact of Proband Indication for Genetic Testing on the Uptake of Cascade Testing Among Relatives

The Impact of Proband Indication for Genetic Testing on the Uptake of Cascade Testing Among Relatives

A Focus Group Study of Perceptions of Genetic Risk Disclosure in Members of the Public in Sweden: “I’ll Phone the Five Closest Ones, but What Happens to the Other Ten?”

Web-Based Tool (FH Family Share) to Increase Uptake of Cascade Testing for Familial Hypercholesterolemia: Development and Evaluation

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