Biomedical subjects

Carol R Horowitz

Publications and source records attributed to Carol R Horowitz.

5 recordsLinked to original sources

PubMed2026

Recommendations for return of secondary genomic findings in observational cohort studies.

The return of secondary genomic findings (ROSF) to participants in observational cohort studies has evolved from a topic of debate to an accepted standard. This Perspective synthesizes the proceedings of a 2024 National Heart, Lung and Blood Institute-sponsored workshop and the broader literature to provide updated guidance for ROSF. Building on the 2010 National Heart, Lung and Blood Institute Working Group recommendations and the 2014 Clinical Sequencing Exploratory Research/Electronic Medical Records and Genomics 'floor and ceiling' framework, we address four areas: an integrated ethical framework for observational cohort settings; the emerging challenge of returning novel result types beyond monogenic variants, including polygenic risk scores, somatic mosaicism and pharmacogenomic findings; health equity and community engagement as structural prerequisites for ethical ROSF; and scalability challenges, including technology-assisted disclosure. Drawing on implementation experience from large-scale sequencing programs, we offer recommendations that balance researcher obligations with participant autonomy and equitable access to the benefits of genomic research.

Journal Article↗

PubMed2026

"Will it be enough to be respected?": understanding personal, institutional, and societal harms and benefits of genomics research.

BACKGROUND: Transgender Identity Genomics Research (TIGR)-research examining potential associations between genetic factors and transgender, nonbinary, and gender diverse (trans) identities-takes place in a complex landscape with significant potential to either benefit or harm trans communities. As public and political scrutiny of trans communities intensifies, the stakes and potential impacts of TIGR are heightened and ethical, legal and social implications must be considered. To better understand how those who would be most affected by TIGR view such research, we explored trans adults' perceptions of TIGR in the current environment and how they perceive TIGR may impact their futures. METHODS: Using a community-based participatory research approach, we partnered with a trans-led Executive Stakeholder Board to conduct in-depth interviews with 31 trans adults in the United States between June-December 2024 and conducted a Reflexive Thematic Analysis. RESULTS: Participants (mean age=34 years, range=19-73 years; 61% people of color; 39% nonbinary, 39% transgender women, 22% transgender men) identified possible benefits of TIGR such as personal affirmation, increased social acceptance, and improved access to gender-affirming healthcare. They also expressed concerns about potential harms, including further stigmatization, discrimination, and pathologization of trans identities. While most viewed research in trans communities (including TIGR) as a net positive, some participants felt it less useful compared to addressing more urgent, material challenges trans communities face. CONCLUSION: Our findings underscore that TIGR, like all scientific research, is shaped by the sociopolitical environment. It is imperative that TIGR researchers engage meaningfully and ethically with trans communities to minimize potential harms and center community needs.

Genetics↗

PubMed2026

Genotype-Guided Antidepressant Prescribing for Patients With Depression: A Randomized Clinical Trial.

IMPORTANCE: The effectiveness of pharmacogenetics to guide prescribing of selective serotonin reuptake inhibitors (SSRIs) for depression remains unclear, despite the well-established association between SSRI pharmacokinetics and genetic variation. OBJECTIVE: To determine whether pharmacogenetic-guided prescribing of SSRIs improves treatment response in patients with depression. DESIGN, SETTING, AND PARTICIPANTS: The ADOPT PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) Depression pragmatic randomized clinical trial was conducted from August 10, 2021, through April 27, 2024, at primary care, psychiatry, or family medicine clinics at enrolling sites throughout the US. Patients were aged 8 years or older and had experienced depression for 3 months or longer. INTERVENTION: Patients were randomized to genotype-guided SSRI prescribing (intervention group) or usual care (control group). Actionable drug metabolism phenotypes were defined as those for which pharmacogenetic clinical guidelines recommend alternative medication selection or dose adjustment. MAIN OUTCOMES AND MEASURES: The primary outcome was change in Patient-Reported Outcomes Measurement Information System (PROMIS) depression T scores at 3 months among patients with the actionable phenotype. Secondary end points included adverse effect severity of SSRIs at 3 months and depression remission (measured with PROMIS depression scores and Patient Health Questionnaire-8 [PHQ-8] scores) at 6 months. RESULTS: This study of 1460 patients included 1239 adults (84.9%) (mean [SD] age, 40.6 [16.7] years) and 221 children (15.1%) (mean [SD] age, 14.6 [1.8] years). Most patients were female (1096 [75.1%]). A total of 692 patients (47.4%) had an actionable phenotype; 351 (50.7%) were assigned to the intervention, and 341 (49.3%) were assigned to usual care. At baseline, 463 of the 692 patients (66.9%) reported having depressive symptoms for more than 2 years, 603 (87.1%) were receiving pharmacologic treatment, and 354 (51.2%) were receiving nonpharmacologic treatment. At 3 months, no significant differences were observed between the intervention and usual care groups in change in PROMIS depression T scores (mean [SD] change, -4.3 [8.4] vs -4.0 [8.1]; P = .68), medication adverse effect burden (mean [SD] change, 8.2 [4.3] vs 7.8 [4.5]; P = .37), or Patient Health Questionnaire-8 score change (mean [SD] change, -3.3 [5.2] vs -2.7 [4.8]; P  = .13). However, at 6 months, the PROMIS depression T-score remission rate (score ≤16) was higher in the intervention group compared with the usual care group (153 of 317 patients [48.3%] vs 122 of 310 patients [39.4%]; P = .02). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, genotype-guided prescribing of SSRIs did not improve control of depression symptoms at 3 months compared with usual care but was associated with higher depression remission rates at 6 months. These findings suggest a possible longer-term clinical benefit and indicate that future studies should focus on the durability and long-term impact of genotype-guided prescribing in the management of depressive symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04445792 (Master Protocol Research Program platform trial) and NCT05966155 (ADOPT PGx Depression trial).

Humans↗

PubMed2026

Blood mitochondrial heteroplasmic variants and cognitive performance in late midlife: REGARDS study.

BACKGROUND: Studies linking mitochondrial DNA (mtDNA) variants to cognition yielded inconsistent findings, and the underlying mechanisms remain unclear. We investigated whether mtDNA heteroplasmic variants were associated with cognitive outcomes, including the Montreal Cognitive Assessment (MoCA), in 197 late midlife adults from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort with complete data. METHODS: MtDNA was sequenced from blood using targeted deep sequencing. Adjusted linear and mixed-effects models examined the associations by functional regions, genes, total variant burden, nonsynonymous variants, and control regions. RESULTS: Heteroplasmic variants in the control region (β = -0.44, 95% CI: -0.83, -0.05, p = 0.027) and transfer RNA (tRNA) genes (β = -1.34, 95% CI: -2.58, -0.11, p = 0.034) were associated with MoCA baseline scores. Individual variants in cytochrome c oxidase subunit 1 (CO1) (β = -1.51, 95% CI: -2.54, -0.47, p = 0.005), NADH dehydrogenase subunit 1 (ND1) (β = -2.63, 95% CI: -4.56, -0.70, p = 0.008), and Displacement Loop (D-LOOP2) (β = -2.25, 95% CI: -4.20, -0.30, p = 0.025) was associated with reduced baseline MoCA scores. The ND6 (β = −1.23, 95% CI: −2.09, − 0.37, p = 0.006), ND4 (β = −1.11, 95% CI: −2.02, − 0.20, p = 0.018), ATP Synthase Membrane Subunit 8 (ATP8; β = −1.38, 95% CI: −2.63, − 0.13, p = 0.031), and D-LOOP1 (β = −0.61, 95% CI: −1.20, − 0.01, p = 0.045) genes suggested a potential association with executive function. Longitudinal Animal Fluency Test (AFT) scores were inversely associated with heteroplasmic variants in coding regions (β = -0.10, 95% CI: -0.19, -0.006, p = 0.049), the total number of variants (β = -0.06, 95% CI: -0.11, -0.003, p = 0.037) and total nonsynonymous variants (β = -0.11, 95% CI: -0.21, -0.01, p = 0.040). Variants in the control region were associated with the greatest decline in verbal fluency (β = −0.20, 95% CI: −0.39 to − 0.002, p = 0.049). No associations were observed between mitochondrial variants and verbal memory performance or the MoCA composite scores. CONCLUSIONS: Our study indicates that mitochondrial variants measured in blood may provide insight into cognitive function during midlife. However, additional studies are needed to validate these associations and to address potential power limitations in our study.

Humans↗

PubMed2025

Genomic sequencing in diverse and underserved pediatric populations: Parent perspectives on understanding, uncertainty, psychosocial impact, and personal utility of results.

PURPOSE: Limited evidence evaluates parents' perceptions of their child's clinical genome-scale sequencing (GS) results, particularly among individuals from medically underserved groups. Five Clinical Sequencing Evidence-Generating Research consortium studies performed GS in children with suspected genetic conditions with high proportions of individuals from underserved groups to address this evidence gap. METHODS: Parents completed surveys of perceived understanding, personal utility, and test-related distress after GS result disclosure. We assessed outcomes' associations with child- and parent-related factors: child age; type of GS finding; and parent health literacy, numeracy, and education. RESULTS: A total of 1763 parents completed surveys; 83% met "underserved" criteria based on race, ethnicity, and risk factors for barriers to access. We observed high perceived understanding and personal utility and low test-related distress. Outcomes were associated with the type of GS finding; parents of children with a pathogenic or likely pathogenic finding endorsed higher personal utility and more test-related distress than those whose children had a variant of uncertain significance or normal finding. Personal utility was higher in parents who met the criteria for "underserved." CONCLUSION: Our findings shed light on correlates of parents' cognitive and emotional responses to their child's GS findings and emphasize the need for tailored support in disclosure discussions.

Humans↗