Dataset Information

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.

ABSTRACT:

Objective or purpose

Primary open-angle glaucoma (POAG) is a highly heritable disease with 127 identified risk loci. Polygenic risks score (PRS) offers a measure of aggregate genetic burden. In this study, we assess whether PRS improves risk stratification in patients with ocular hypertension.

Design

A post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS) data.

Setting participants and/or controls

1636 participants were followed from 1994 to 2020 across 22 sites. The PRS was computed for 1009 OHTS participants using summary statistics from largest cross-ancestry POAG metanalysis with weights trained using 8,813,496 variants from 488,395 participants in the UK Biobank.

Methods interventions or testing

Survival regression analysis, with endpoint as development of POAG, predicted disease onset from PRS incorporating baseline covariates.

Main outcomes and measures

Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent AUC were used to compare the predictive performance of multivariable Cox-Proportional Hazards models.

Results

Mean PRS was significantly higher for POAG-converters (0.24 ± 0.95) than for non-converters (-0.12 ± 1.00) (p < 0.01). POAG risk increased 1.36% with each higher PRS decile, with conversion ranging from 9.5% in the lowest PRS decile to 21.8% in the highest decile. Comparison of low- and high-risk PRS tertiles showed a 1.8-fold increase in 20-year POAG risk for participants of European and African ancestries (p<0.01). In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year decrease in age at diagnosis, (p=0.05). No significant linear relationship between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C-index = 0.77) compared to OHTS baseline model (C-index=0.75) (p<0.01). One standard deviation higher PRS conferred a mean hazard ratio of 1.25 (CI=[1.13, 1.44]) for POAG onset.

Conclusions

Higher PRS is associated with increased risk for, and earlier development of POAG in patients with ocular hypertension. Early treatment may mitigate the risk from high genetic burden, delaying clinically detectable disease by up to 5.2 years. The inclusion of a PRS improves the prediction of POAG onset.

SUBMITTER: Singh RK

PROVIDER: S-EPMC10462203 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.

Singh Rishabh K RK Zhao Yan Y Elze Tobias T Fingert John J Gordon Mae M Kass Michael A MA Luo Yuyang Y Pasquale Louis R LR Scheetz Todd T Segrè Ayellet V AV Wiggs Janey L JL Zebardast Nazlee N

medRxiv : the preprint server for health sciences 20230816

<h4>Objective or purpose</h4>Primary open-angle glaucoma (POAG) is a highly heritable disease with 127 identified risk loci. Polygenic risks score (PRS) offers a measure of aggregate genetic burden. In this study, we assess whether PRS improves risk stratification in patients with ocular hypertension.<h4>Design</h4>A post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS) data.<h4>Setting participants and/or controls</h4>1636 participants were followed from 1994 to 2020 across 22 sit ...[more]

PMID: 37645858

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Project description:ImportancePrimary open-angle glaucoma (POAG) is a highly heritable disease, with 127 identified risk loci to date. Polygenic risk score (PRS) may provide a clinically useful measure of aggregate genetic burden and improve patient risk stratification.ObjectiveTo assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension.Design, setting, and participantsThis was a post hoc analysis of the Ocular Hypertension Treatment Study. Data were collected from 22 US sites with a mean (SD) follow-up of 14.0 (6.9) years. A total of 1636 participants were followed up from February 1994 to December 2008; 1077 participants were enrolled in an ancillary genetics study, of which 1009 met criteria for this analysis. PRS was calculated using summary statistics from the largest cross-ancestry POAG meta-analysis, with weights trained using 8 813 496 variants from 449 186 cross-ancestry participants in the UK Biobank. Data were analyzed from July 2022 to December 2023.ExposuresFrom February 1994 to June 2002, participants were randomized to either topical intraocular pressure-lowering medication or close observation. After June 2002, both groups received medication.Main outcomes and measuresOutcome measures were hazard ratios for POAG onset. Concordance index and time-dependent areas under the receiver operating characteristic curve were used to compare the predictive performance of multivariable Cox proportional hazards models.ResultsOf 1009 included participants, 562 (55.7%) were female, and the mean (SD) age was 55.9 (9.3) years. The mean (SD) PRS was significantly higher for 350 POAG converters (0.24 [0.95]) compared with 659 nonconverters (-0.12 [1.00]) (P < .001). POAG risk increased 1.36% (95% CI, 1.08-1.64) with each higher PRS decile, with conversion ranging from 9.52% (95% CI, 7.09-11.95) in the lowest PRS decile to 21.81% (95% CI, 19.37-24.25) in the highest decile. Comparison of low-risk and high-risk PRS tertiles showed a 2.0-fold increase in 20-year POAG risk for participants of European and African ancestries. In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year (95% CI, 0.01-1.03) decrease in age at diagnosis (P = .047). No significant linear association between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C index = 0.77) compared with the Ocular Hypertension Treatment Study baseline model (C index = 0.75) (P < .001). Each 1-SD higher PRS conferred a mean hazard ratio of 1.25 (95% CI, 1.13-1.44) for POAG onset.Conclusions and relevanceHigher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset.Trial registrationClinicalTrials.gov Identifier: NCT00000125.

Project description:IntroductionFixed-combination intraocular pressure (IOP)-lowering medications simplify treatment regimens for patients requiring 2 ocular hypotensive agents to maintain sufficiently low IOP. The aim of this study was to evaluate the safety and efficacy of fixed-combination brinzolamide 1%/brimonidine 0.2% (BBFC) versus concomitant administration of brinzolamide 1% plus brimonidine 0.2% (BRINZ + BRIM) in patients with open-angle glaucoma or ocular hypertension.MethodsThis was a prospective, phase 3, multicenter, double-masked, 6-month trial. Patients who had insufficient IOP control with monotherapy or who were receiving 2 IOP-lowering medications were randomized 1:1 to receive twice-daily BBFC or BRINZ + BRIM. IOP was assessed at 9 a.m. and 11 a.m. during week 2, week 6, month 3, and month 6 visits. The primary efficacy endpoint was mean diurnal IOP change from baseline to month 3; noninferiority was concluded if the upper limit of the 95% CI of the between-group difference was <1.5 mmHg. Supportive endpoints included mean IOP, IOP change from baseline, and percentage of patients with IOP <18 mmHg. Adverse events were recorded.ResultsThe mean diurnal IOP change from baseline with BBFC (least squares mean ± standard error -8.5 ± 0.16 mmHg) was noninferior to that with BRINZ + BRIM (-8.3 ± 0.16 mmHg; mean difference -0.1 mmHg; 95% CI -0.5 to 0.2 mmHg). The upper limits of the 95% CIs were <1.5 mmHg at all time points. Decreases from baseline >8 mmHg were observed for least squares mean diurnal IOP in both groups as early as week 2 and continued to the end of the study. The results of all other supportive endpoints were similar to the primary efficacy endpoint. The most common ocular adverse drug reactions were hyperemia of the eye (reported as ocular or conjunctival hyperemia), visual disturbances, ocular allergic reactions, and ocular discomfort. Common systemic adverse drug reactions included dysgeusia, oral dryness, and fatigue/drowsiness.ConclusionBrinzolamide 1%/brimonidine 0.2% fixed combination was as well tolerated and effective as concomitant therapy with its components. BBFC reduces treatment burden in patients who require multiple IOP-lowering medications.

Project description:PurposeTo quantify patients' preferences for glaucoma outcomes and use this information to prioritize outcomes that are important to patients.DesignA cross-sectional study using best-worst scaling object case (BWS).ParticipantsTwo hundred seventy-four participants newly diagnosed with ocular hypertension or mild to moderate open angle glaucoma from three private practices and one academic medical center in the United States.MethodsWe designed a preference-elicitation survey based on findings from 25 semi-structured, qualitative interviews with patients with glaucoma (reported elsewhere). The survey asked participants to rate the importance of 13 glaucoma outcomes on a Likert scale as a warm-up exercise followed by completion of 13 BWS tasks. For each task, we presented participants a subset of four outcomes from the possible thirteen, and participants chose the most important and least important outcome. Outcomes included in the survey pertain to maintaining ability to perform vision-dependent activities of daily living (e.g., driving), maintaining visual function and perception (e.g., depth perception), minimizing need to take glaucoma drops, not experiencing ocular surface symptoms (e.g., red eyes, teary eyes), and having adequate control of intraocular pressure (IOP). We administered the survey online and analyzed response patterns using conditional logistic regression to determine the relative importance of different outcomes.Main outcomeOrdinal ranking of glaucoma outcomes based on preference weights.ResultsBetween September 1, 2017 and February 28, 2018, we invited 1035 patients to complete our survey, among whom 274 (26%) responded. Most participants were older than 65 years of age (146/274, 53%) and currently on IOP-lowering drops (179/274, 65%). Participants identified that outcomes with the largest relative importance weight were having "adequate IOP control" and ability to "drive a car during the day," and the outcomes with the smallest relative importance weights were "maintaining appearance of the eye" and "reducing the number of IOP-lowering drops".ConclusionsDetermining the relative importance of glaucoma outcomes to patients can help researchers design studies that may better inform clinical and regulatory decision-making. Although IOP is an outcome that researchers often measure in glaucoma clinical trials, patients also prioritized outcomes related to the ability to perform vision-dependent activities such as driving.

Dataset Information

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.

Objective or purpose

Design

Setting participants and/or controls

Methods interventions or testing

Main outcomes and measures

Results

Conclusions

Publications

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.

Similar Datasets

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