Cases in Precision Medicine: Genetic Testing to Predict Future Risk for Disease in a Healthy Patient

Genetic testing is performed more routinely in clinical practice, and direct-to-consumer tests are widely available. It has obvious appeal as a preventive health measure. Clinicians and their healthy patients increasingly inquire about genetic testing as a tool for predicting diseases, such as cancer, heart disease, or dementia. Despite demonstrated utility for diagnosis in the setting of many diseases, genetic testing still has many limitations as a predictive tool for healthy persons. This article uses a hypothetical case to review key considerations for predictive genetic testing.

Artificial Intelligence and Data Mining to Assess Lung Cancer Risk: Challenges and Opportunities

Preventing Hospital Readmission for Patients With Comorbid Substance Use Disorder: A Randomized Trial: Annals of Internal Medicine: Vol 174, No 7

Background: Hospitalized patients with comorbid substance use disorders (SUDs) are at high risk for poor outcomes, including readmission and emergency department (ED) use. Objective: To determine whether patient navigation services reduce hospital readmissions. Design: Randomized controlled trial comparing Navigation Services to Avoid Rehospitalization (NavSTAR) versus treatment as usual (TAU). (ClinicalTrials.gov: NCT02599818) Setting: Urban academic hospital in Baltimore, Maryland, with an SUD consultation service. Participants: 400 hospitalized adults with comorbid SUD (opioid, cocaine, or alcohol). Intervention: NavSTAR used proactive case management, advocacy, service linkage, and motivational support to resolve internal and external barriers to care and address SUD, medical, and basic needs for 3 months after discharge. Measurements: Data on inpatient readmissions (primary outcome) and ED visits for 12 months were obtained for all participants via the regional health information exchange. Entry into SUD treatment, substance use, and related outcomes were assessed at 3-, 6-, and 12-month follow-up. Results: Participants had high levels of acute care use: 69% had an inpatient readmission and 79% visited the ED over the 12-month observation period. Event rates per 1000 person-days were 6.05 (NavSTAR) versus 8.13 (TAU) for inpatient admissions (hazard ratio, 0.74 [95% CI, 0.58 to 0.96]; P = 0.020) and 17.66 (NavSTAR) versus 27.85 (TAU) for ED visits (hazard ratio, 0.66 [CI, 0.49 to 0.89]; P = 0.006). Participants in the NavSTAR group were less likely to have an inpatient readmission within 30 days than those receiving TAU (15.5% vs. 30.0%; P < 0.001) and were more likely to enter community SUD treatment after discharge (P = 0.014; treatment entry within 3 months, 50.3% NavSTAR vs. 35.3% TAU). Limitation: Single-site trial, which limits generalizability. Conclusion: Patient navigation reduced inpatient readmissions and ED visits in this clinically challenging sample of hospitalized patients with comorbid SUDs. Primary Funding Source: National Institute on Drug Abuse.

A Double-Blind, Randomized, Placebo-Controlled Phase 1 Study of Ad26.ZIKV.001, an Ad26-Vectored Anti–Zika Virus Vaccine

Background: Zika virus (ZIKV) may cause severe congenital disease after maternal–fetal transmission. No vaccine is currently available. Objective: To assess the safety and immunogenicity of Ad26.ZIKV.001, a prophylactic ZIKV vaccine candidate. Design: Phase 1 randomized, double-blind, placebo-controlled clinical study. (ClinicalTrials.gov: NCT03356561) Setting: United States. Participants: 100 healthy adult volunteers. Intervention: Ad26.ZIKV.001, an adenovirus serotype 26 vector encoding ZIKV M-Env, administered in 1- or 2-dose regimens of 5 × 1010 or 1 × 1011 viral particles (vp), or placebo. Measurements: Local and systemic adverse events; neutralization titers by microneutralization assay (MN50) and T-cell responses by interferon-γ enzyme-linked immunospot and intracellular cytokine staining; and protectivity of vaccine-induced antibodies in a subset of participants through transfer in an exploratory mouse ZIKV challenge model. Results: All regimens were well tolerated, with no safety concerns identified. In both 2-dose regimens, ZIKV neutralizing titers peaked 14 days after the second vaccination, with geometric mean MN50 titers (GMTs) of 1065.6 (95% CI, 494.9 to 2294.5) for 5 × 1010 vp and 956.6 (595.8 to 1535.8) for 1 × 1011 vp. Titers persisted for at least 1 year at a GMT of 68.7 (CI, 26.4–178.9) for 5 × 1010 vp and 87.0 (CI, 29.3 to 258.6) for 1 × 1011 vp. A 1-dose regimen of 1 × 1011 vp Ad26.ZIKV.001 induced seroconversion in all participants 56 days after the first vaccination (GMT, 103.4 [CI, 52.7 to 202.9]), with titers persisting for at least 1 year (GMT, 90.2 [CI, 38.4 to 212.2]). Env-specific cellular responses were induced. Protection against ZIKV challenge was observed after antibody transfer from participants into mice, and MN50 titers correlated with protection in this model. Limitation: The study was conducted in a nonendemic area, so it did not assess safety and immunogenicity in a flavivirus-exposed population. Conclusion: The safety and immunogenicity profile makes Ad26.ZIKV.001 a promising candidate for further development if the need reemerges. Primary Funding Source: Janssen Vaccines and Infectious Diseases.

COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study of 8 Million Adults

Race and the False Precision of Glomerular Filtration Rate Estimates

Testing for Primary Aldosteronism and Mineralocorticoid Receptor Antagonist Use Among U.S. Veterans: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 174, No 3

Background: Primary aldosteronism is a common cause of treatment-resistant hypertension. However, evidence from local health systems suggests low rates of testing for primary aldosteronism. Objective: To evaluate testing rates for primary aldosteronism and evidence-based hypertension management in patients with treatment-resistant hypertension. Design: Retrospective cohort study. Setting: U.S. Veterans Health Administration. Participants: Veterans with apparent treatment-resistant hypertension (n = 269 010) from 2000 to 2017, defined as either 2 blood pressures (BPs) of at least 140 mm Hg (systolic) or 90 mm Hg (diastolic) at least 1 month apart during use of 3 antihypertensive agents (including a diuretic), or hypertension requiring 4 antihypertensive classes. Measurements: Rates of primary aldosteronism testing (plasma aldosterone–renin) and the association of testing with evidence-based treatment using a mineralocorticoid receptor antagonist (MRA) and with longitudinal systolic BP. Results: 4277 (1.6%) patients who were tested for primary aldosteronism were identified. An index visit with a nephrologist (hazard ratio [HR], 2.05 [95% CI, 1.66 to 2.52]) or an endocrinologist (HR, 2.48 [CI, 1.69 to 3.63]) was associated with a higher likelihood of testing compared with primary care. Testing was associated with a 4-fold higher likelihood of initiating MRA therapy (HR, 4.10 [CI, 3.68 to 4.55]) and with better BP control over time. Limitations: Predominantly male cohort, retrospective design, susceptibility of office BPs to misclassification, and lack of confirmatory testing for primary aldosteronism. Conclusion: In a nationally distributed cohort of veterans with apparent treatment-resistant hypertension, testing for primary aldosteronism was rare and was associated with higher rates of evidence-based treatment with MRAs and better longitudinal BP control. The findings reinforce prior observations of low adherence to guideline-recommended practices in smaller health systems and underscore the urgent need for improved management of patients with treatment-resistant hypertension. Primary Funding Source: National Institutes of Health.

Calling a Code

Effects of Intensive Blood Pressure Treatment on Orthostatic Hypotension: A Systematic Review and Individual Participant–based Meta-analysis: Annals of Internal Medicine: Vol 174, No 1

Background: Although intensive blood pressure (BP)–lowering treatment reduces risk for cardiovascular disease, there are concerns that it might cause orthostatic hypotension (OH). Purpose: To examine the effects of intensive BP-lowering treatment on OH in hypertensive adults. Data Sources: MEDLINE, EMBASE, and Cochrane CENTRAL from inception through 7 October 2019, without language restrictions. Study Selection: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) that involved more than 500 adults with hypertension or elevated BP and that were 6 months or longer in duration. Trial comparisons were groups assigned to either less intensive BP goals or placebo, and the outcome was measured OH, defined as a decrease of 20 mm Hg or more in systolic BP or 10 mm Hg or more in diastolic BP after changing position from seated to standing. Data Extraction: 2 investigators independently abstracted articles and rated risk of bias. Data Synthesis: 5 trials examined BP treatment goals, and 4 examined active agents versus placebo. Trials examining BP treatment goals included 18 466 participants with 127 882 follow-up visits. Trials were open-label, with minimal heterogeneity of effects across trials. Intensive BP treatment lowered risk for OH (odds ratio, 0.93 [95% CI, 0.86 to 0.99]). Effects did not differ by prerandomization OH (P for interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged. Limitations: Assessments of OH were done while participants were seated (not supine) and did not include the first minute after standing. Data on falls and syncope were not available. Conclusion: Intensive BP-lowering treatment decreases risk for OH. Orthostatic hypotension, before or in the setting of more intensive BP treatment, should not be viewed as a reason to avoid or de-escalate treatment for hypertension. Primary Funding Source: National Heart, Lung, and Blood Institute, National Institutes of Health. (PROSPERO: CRD42020153753)

Racism and Health in the United States: A Policy Statement From the American College of Physicians

Racial minorities in the United States have reported experiencing widespread racism throughout all aspects of life, from housing to education to employment. Existing research has examined the role of racism, discrimination, and violence in one's interaction with the health care system and their association with poorer mental and physical health. Systemic racism that underlies the fabric of society often manifests itself in prominent institutions, such as law enforcement agencies, regardless of individual intent. Overt and covert racist laws and policies, personal implicit biases, and other factors result in Black individuals and other people of color being the subject of law enforcement violence and criminal justice system interactions at disproportionately high rates. The demonstrated association between discriminatory law enforcement practices and violence and personal and community health necessitates treating these issues as public health issues worthy of a public policy intervention. Addressing some of the sources of institutional racism and harm through transparency and accountability measures is the first of many steps required to begin correcting historical racial injustices.