The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients

Abstract

Background Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase healthcare utilization without clinical value. Objective Describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care. Design Pilot randomized trial. Setting Academic primary care practices. Participants Nine primary care physicians (PCPs) and 100 generally healthy patients aged 40–65. Interventions Patients were randomly assigned to receive a family history report alone (FH arm) or in combination with an interpreted WGS report including monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits (FH+WGS arm). Each patient met with his or her PCP to discuss the reports. Measurements Clinical outcomes and healthcare utilization through six months were obtained from audio-recorded PCP-patient discussions and medical records. Patients’ health behavior changes were surveyed six months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results. Results Mean age was 55 years; 58% were female. Eleven FH+WGS patients (22%, 12%–36%) had new MDR results. Only two (4%, 0.01%–14%) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). PCPs recommended new clinical actions for 16% (8%–30%) of FH patients and 34% (22%–49%) of FH+WGS patients. Thirty (17%–45%) and 41% (27%–56%) of FH and FH+WGS patients, respectively, reported making a health behavior change after six months. Geneticists rated PCP management of eight MDR results (73%, 39%–99%) as appropriate and two (18%, 3%–52%) as inappropriate. Limitations Limited sample size and ancestral and socioeconomic diversity. Conclusions Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Non-geneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value. Registration ClinicalTrials.gov identifier NCT01736566 Funding National Institutes of Health

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

“…Coupled with growing knowledge of how such genomic variation relates to health, disease and treatment options, these findings suggest that whole genome sequencing can benefit routine health care in Canada's future. Despite a considerable burden of uncertainty, and the possibility that falsepositive findings may engender follow-up investigations 51 and a "worried well" population, 70 incorporation of sequence-based family history should serve to enhance personalized patient care. somal), Neal Sondheimer (mitochondrial) and Iris Cohn (pharmacogenomics) interpreted the genomic variants.…”

“…40 This variant was recently interpreted as likely pathogenic in another healthy cohort. 51 However, it is as frequent as 0.1% in some populations (http://gnomad.broadinstitute.org/), which suggests that the variant is either unrelated to disease or functions with incomplete penetrance. Additional variants, as observed in CDH1, CHMP2B and KCNE2, have been published as disease alleles, with functional support, albeit with discordance in the literature and databases.…”

The Value of Pharmacogenomic Information

“…In addition, it is increasingly clear that what happens downstream of genetic testing is also a critical determinant of payers' skepticism (Kohane, Hsing, and Kong 2012;Vassy et al 2017). For example, a 2005 randomized controlled trial of genetic testing for Alzheimer's disease found that individuals who tested positive were 5.76 times more likely to adjust their long-term insurance plans (Zick et al 2005).…”

Analysis of Problems of Implementation of the Priority Direction of «personalized Medicine» in the Format of Full Project Cycle

“…Опубликованные в 2017 г. результаты дру-гого исследования ставит под сомнение це-лесообразность использования технологии полного секвенирования генома в рамках оказания первичной медицинской помощи [26]. С участием 100 здоровых пациентов 40-65 лет и их лечащих врачей было сделано полногеномное секвенирование для половины участников экспертимента.…”

“…При этом, несмотря на выявленные мутации, видимых нарушений состояния здоровья испытуемых обнаружено не было. Хотя ученые по-прежнему оптими-стично настроены в отношении применения технологии CRISPR-Cas9, они рекомендуют своим коллегам более внимательно изучать внецелевые эффекты любого редактирования генов.Опубликованные в 2017 г. результаты дру-гого исследования ставит под сомнение це-лесообразность использования технологии полного секвенирования генома в рамках оказания первичной медицинской помощи [26]. С участием 100 здоровых пациентов 40-65 лет и их лечащих врачей было сделано полногеномное секвенирование для половины участников экспертимента.…”