IMPORTANCE: Irreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage ...disease. As a consequence, large numbers of individuals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk individuals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma. OBJECTIVE: To assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022. MAIN OUTCOMES AND MEASURES: The association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields. RESULTS: A total of 1777 eyes from 896 individuals had sufficient data for structural progression analyses and 1563 eyes from 808 individuals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 individuals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. Individuals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5; 95% CI, 1.13-1.97; P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52; 95% CI, 0.28-0.96; P = .04). CONCLUSIONS AND RELEVANCE: In this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify individuals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.
Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank ...participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10
). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
Nephrotoxic medication exposure represents a common cause of acute kidney injury (nephrotoxin-AKI) in hospitalized children. Systematic serum creatinine (SCr) screening has not been routinely ...performed in children receiving nephrotoxins, potentially leading to underestimating nephrotoxin-AKI rates. We aimed to accurately determine nephrotoxin exposure and nephrotoxin-AKI rates to drive appropriate interventions in non-critically ill hospitalized children.
We conducted a prospective quality improvement project implementing a systematic electronic health record (EHR) screening and decision support process (trigger) at a single quaternary pediatric hospital. Patients were all noncritically ill hospitalized children receiving an intravenous aminoglycoside for ≥3 days or ≥3 nephrotoxins simultaneously (exposure). Pharmacists recommended daily SCr monitoring in exposed patients. AKI was defined by the modified pediatric Risk, Injury, Failure, Loss and End-stage Renal Disease criteria (≥25% decrease in estimated creatinine clearance). We developed 4 novel metrics: exposure rate per 1000 patient-days, AKI rate per 1000 patient-days, AKI rate (%) per high nephrotoxin admission, and AKI days per 100 exposure days (AKI intensity).
This study included 21 807 patients accounting for 27 711 admissions. A total of 726 (3.3%) unique exposed patients accounted for 945 hospital admissions (6713 patient-days). AKI occurred in 25% of unique exposed patients and 31% of exposure admissions (1974 patient-days). Our EHR-driven SCr nephrotoxin-AKI surveillance process was associated with a 42% reduction in AKI intensity.
Nephrotoxin-AKI rates are high in noncritically ill children; systematic screening for nephrotoxic medication exposure and AKI detection was accomplished reliably through an EHR based trigger tool.
To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma.
Prospective, observational cohort study.
Participants from the ...Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment.
A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment.
Commencement or escalation of IOP-lowering therapy.
A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio HR, 1.45 per 1 standard deviation /SD; 95% confidence interval CI, 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001).
This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma.
Proprietary or commercial disclosure may be found after the references.
Purpose
To evaluate the association between localised vascular and retinal nerve fibre layer (RNFL) loss and genetic risk for glaucoma and cardiovascular disease using polygenic risk scores (PRS).
...Methods
858 eyes were included from 455 individuals with suspect and early manifest primary open angle glaucoma. Eyes were characterised as having localised vascular and/or RNFL wedge‐shaped defects by scrutiny of optical coherence tomography angiography (OCTA) and OCT images, respectively. Investigations included associations with pre‐established scores for genetic risk of glaucoma and cardiovascular disease in the context of glaucoma risk factors and systemic vascular disease outcomes.
Results
Higher genetic risk for glaucoma was associated with both vascular wedge defects and RNFL defects (p < 0.001 and p = 0.020, respectively). A greater genetic risk of glaucoma was associated with the presence of multiple vascular wedges per eye (p = 0.005). Glaucoma progression based on global RNFL loss was associated with vascular and RNFL wedge defects (p ≤ 0.001 and p = 0.008, respectively). The glaucoma PRS was significantly associated with vascular, but not RNFL, wedge defects after controlling for disc haemorrhage (p = 0.007 and p = 0.070, respectively). Vascular wedge defects were not related to the cardiovascular PRS.
Conclusion
Individuals with a higher genetic risk of glaucoma based on the PRS were more likely to have retinal vascular defects, as well as structural glaucomatous loss, but this did not relate to systemic cardiovascular risk. This possibly implies a local pathophysiology for the vascular defects in some cases, which may have clinical relevance in the early stages of glaucoma and in individuals at high genetic risk.
To assess the association between physical activity and spectral-domain optical coherence tomography (SD-OCT)-measured rates of macular thinning in an adult population with primary open-angle ...glaucoma.
The correlation between accelerometer-measured physical activity and rates of macular ganglion cell-inner plexiform layer (GCIPL) thinning was measured in 735 eyes from 388 participants of the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study. The association between accelerometer-measured physical activity and cross-sectional SD-OCT macular thickness was then assessed in 8862 eyes from 6152 participants available for analysis in the UK Biobank who had SD-OCT, ophthalmic, comorbidity, and demographic data.
Greater physical activity was associated with slower rates of macular GCIPL thinning in the PROGRESSA study (beta = 0.07 µm/y/SD; 95% confidence interval CI, 0.03-0.13; P = 0.003) after adjustment for ophthalmic, demographic and systemic predictors of macular thinning. This association persisted in subanalyses of participants characterized as glaucoma suspects (beta = 0.09 µm/y/SD; 95% CI, 0.03-0.15; P = 0.005). Participants in the upper tertile (greater than 10,524 steps/d) exhibited a 0.22-µm/y slower rate of macular GCIPL thinning than participants in the lower tertile (fewer than 6925 steps/d): -0.40 ± 0.46 µm/y versus -0.62 ± 0.55 µm/y (P = 0.003). Both time spent doing moderate/vigorous activity and mean daily active calories were positively correlated with rate of macular GCIPL thinning (moderate/vigorous activity: beta = 0.06 µm/y/SD; 95% CI, 0.01-0.105; P = 0.018; active calories: beta = 0.06 µm/y/SD; 95% CI, 0.006-0.114; P = 0.032). Analysis among 8862 eyes from the UK Biobank revealed a positive association between physical activity and cross-sectional total macular thickness (beta = 0.8 µm/SD; 95% CI, 0.47-1.14; P < 0.001).
These results highlight the potential neuroprotective benefits of exercise on the human retina.
The ganglion cell analysis (GCA) of the CIRRUSTM HD-OCT (Carl Zeiss, Meditec; Dublin, CA) provides measurement of the macular ganglion cell-inner plexiform layer (GCIPL) thickness. This study ...determined the frequency of scan artefacts and errors in GCIPL imaging in individuals undergoing HD-OCT surveillance for glaucoma.
A total of 1439 eyes from 721 subjects enrolled in a prospective study assessing predictors of glaucoma progression underwent macular GCIPL imaging with the CIRRUS HD-OCT at recruitment. The prevalence of acquisition errors, segmentation errors, and co-morbid macular pathology was determined.
A total of 87 (6.0%) of the 1439 scans had either acquisition errors, segmentation artefacts, or other macular pathology. The most common co-morbid macular pathology was epiretinal membrane in 2.2% of eyes.
The macular GCIPL scan was artefact free in 94% of eyes. However, epiretinal membrane and high myopia can cause scan artefact and should be considered when interpreting the results.
To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion ...cell-inner plexiform layer (mGCIPL).
Prospective, longitudinal cohort study.
Two hundred seventy-one eyes from 207 individuals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance.
Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis.
Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL.
Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg; 95% confidence interval CI, 2.37-5.43 mmHg; P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 μm; 95% CI, 4.38-9.77 μm; P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03; 95% CI, 1.26-7.28; P = 0.01).
Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.
To evaluate the relationship between body mass index (BMI) and glaucoma progression.
Multicohort observational study.
This study combined a retrospective longitudinal analysis of suspect and early ...manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. The BMI was then associated with glaucoma diagnosis and cross-sectional vertical cup-disc ratio (VCDR) measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study.
In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (mean duration of monitoring (5.28 ± 1.80 years (10.6 ± 3.59 visits) (β 0.04 dB/year/SD95% CI 0.005, 0.069; P = .013). In the UK Biobank, a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (β –0.048/SD 95% CI –0.056, 0.96; P < .001) and a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR 0.90 95% CI 0.84, 0.98; P = .011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR 0.94/SD; 95% CI 0.91, 0.98; P = .002). Body mass index was also positively correlated with intraocular pressure (β 0.11/SD; 95% CI 0.06, 0.15; P < .001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (β –0.007/SD; 95% CI –0.01, –0.001; P = .023).
Body mass index correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.
To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma.
Prospective, longitudinal study of preperimetric and perimetric ...glaucoma.
Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment.
Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients.
OCT and HVF baseline status and longitudinal progression.
After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio OR, 2.70; 95% confidence interval CI, 1.66-4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039).
Cardiovascular disease is an important risk factor for glaucoma progression.
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