The Association between Medication Adherence and Visual Field Progression in the Collaborative Initial Glaucoma Treatment Study.

PURPOSE: To evaluate the relationship between medication adherence and visual field progression in participants randomized to the medication arm of the Collaborative Initial Glaucoma Treatment Study (CIGTS). DESIGN: The CIGTS was a randomized, multicenter clinical trial comparing initial treatment with topical medications to trabeculectomy for 607 participants with newly diagnosed glaucoma. PARTICIPANTS: Three hundred seven participants randomized to the medication arm of the CIGTS. METHODS: Participants were followed up at 6-month intervals for up to 10 years. Self-reported medication adherence and visual fields were measured. Medication adherence was assessed by telephone from responses to the question, "Did you happen to miss any dose of your medication yesterday?" The impact of medication adherence on mean deviation (MD) over time was assessed with a linear mixed regression model adjusting for the effects of baseline MD and age, cataract extraction, interactions, and time (through year 8, excluding time after crossover to surgery). Medication adherence was modeled as a cumulative sum of the number of prior visits where a missed dose of medication was reported. MAIN OUTCOME MEASURE: Mean deviation over time. RESULTS: Three hundred seven subjects (306 with adherence data) were randomized to treatment with topical medications and followed up for an average of 7.3 years (standard deviation, 2.3 years). One hundred forty-two subjects (46%) reported never missing a dose of medication over all available follow-up, 112 patients (37%) reported missing medication at up to one third of visits, 31 patients (10%) reported missing medication at one third to two thirds of visits, and 21 patients (7%) reported missing medication at more than two thirds of visits. Worse medication adherence was associated with loss of MD over time (P = 0.005). For subjects who reported never missing a dose of medication, the average predicted MD loss over 8 years was 0.62 dB, consistent with age-related loss (95% confidence interval [CI], 0.17-1.06; P = 0.007); subjects who reported missing medication doses at one third of visits had a loss of 1.42 dB (95% CI, 0.86-1.98; P < 0.0001); and subjects who reported missing medication doses at two thirds of visits showed a loss of 2.23 dB (95% CI, 1.19-3.26; P < 0.0001). CONCLUSIONS: This longitudinal assessment demonstrated a statistically and clinically significant association between medication nonadherence and glaucomatous vision loss.

Binocular Measures of Visual Acuity and Visual Field versus Binocular Approximations.

PURPOSE: To assess the relationship of binocular visual function tests with binocular approximations using data from the Collaborative Initial Glaucoma Treatment Study (CIGTS). DESIGN: Case series based on existing data from a clinical trial. PARTICIPANTS: Six hundred seven patients with newly diagnosed open-angle glaucoma from the CIGTS. METHODS: Monocular visual field (VF) and visual acuity (VA) tests were performed at baseline and every 6 months thereafter. Binocular tests of visual function (Esterman VF score, binocular VA) were added to the CIGTS protocol 3 years into the study. The binocular approximations of binocular visual function were better or worse eye, average eye, better or worse location, and binocular summation or pointwise binocular summation. Associations between binocular tests and binocular approximations to represent binocular visual function were assessed with Pearson's correlations (r), as was the relationship between vision-related quality of life (VR QOL; Visual Activities Questionnaire [VAQ] and the 25-item National Eye Institute Visual Function Questionnaire [NEI VFQ-25]) and binocular tests or binocular approximations of visual function. MAIN OUTCOME MEASURES: Binocular visual function (VF and VA) and VR QOL. RESULTS: Five hundred seventy-five patients underwent at least 1 binocular visual function test. The Esterman score was correlated significantly with all binocular approximations of VF, with r values ranging from 0.31 (worse-eye mean deviation [MD]) to 0.42 (better-eye MD; P < 0.0001 for all). Binocular VA showed stronger correlations with binocular approximations, with r values ranging from 0.65 (worse-eye VA) to 0.80 (binocular summation; P < 0.0001 for all). Correlations between the VAQ and Esterman score were stronger in 7 of 9 subscales (r = -0.14 to -0.25; P < 0.05 for all) than correlations with all 7 binocular approximations. In contrast, correlations between the VAQ and binocular VA (r = -0.07 to -0.21) were weaker in all subscales than those with better-eye, average-eye, and binocular summation of VA (r = -0.12 to -0.25), but not different from worse-eye values. These trends also were found in relevant subscales of the NEI VFQ-25. CONCLUSIONS: We found limited benefit in binocular testing of VA in the clinical setting as a means of approximating a patient's reported visual functioning. In contrast, we found some benefit in performing binocular VF testing, because the results correlated more closely with reported functioning than binocular approximations.

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹8), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹°). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Genome-wide association study and meta-analysis of intraocular pressure.

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10(-8)). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.

Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma.

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets.

Association of CAV1/CAV2 genomic variants with primary open-angle glaucoma overall and by gender and pattern of visual field loss.

PURPOSE: The CAV1/CAV2 (caveolin 1 and caveolin 2) genomic region previously was associated with primary open-angle glaucoma (POAG), although replication among independent studies has been variable. The aim of this study was to assess the association between CAV1/CAV2 single nucleotide polymorphisms (SNPs) and POAG in a large case-control dataset and to explore associations by gender and pattern of visual field (VF) loss further. DESIGN: Case-control study. PARTICIPANTS: We analyzed 2 large POAG data sets: the Glaucoma Genes and Environment (GLAUGEN) study (976 cases, 1140 controls) and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium (2132 cases, 2290 controls). METHODS: We studied the association between 70 SNPs located within the CAV1/CAV2 genomic region in the GLAUGEN and NEIGHBOR studies, both genotyped on the Illumina Human 660WQuadv1C BeadChip array and imputed with the Markov Chain Haplotyping algorithm using the HapMap 3 reference panel. We used logistic regression models of POAG in the overall population and separated by gender, as well as by POAG subtypes defined by type of VF defect (peripheral or paracentral). Results from GLAUGEN and NEIGHBOR were meta-analyzed, and a Bonferroni-corrected significance level of 7.7 × 10(-4) was used to account for multiple comparisons. MAIN OUTCOME MEASURES: Overall POAG, overall POAG by gender, and POAG subtypes defined by pattern of early VF loss. RESULTS: We found significant associations between 10 CAV1/CAV2 SNPs and POAG (top SNP, rs4236601; pooled P = 2.61 × 10(-7)). Of these, 9 were significant only in women (top SNP, rs4236601; pooled P = 1.59 × 10(-5)). Five of the 10 CAV1/CAV2 SNPs were associated with POAG with early paracentral VF (top SNP, rs17588172; pooled P = 1.07 × 10(-4)), and none of the 10 were associated with POAG with peripheral VF loss only or POAG among men. CONCLUSIONS: CAV1/CAV2 SNPs were associated significantly with POAG overall, particularly among women. Furthermore, we found an association between CAV1/CAV2 SNPs and POAG with paracentral VF defects. These data support a role for caveolin 1, caveolin 2, or both in POAG and suggest that the caveolins particularly may affect POAG pathogenesis in women and in patients with early paracentral VF defects.

Estrogen pathway polymorphisms in relation to primary open angle glaucoma: an analysis accounting for gender from the United States.

PURPOSE: Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender. METHODS: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women. RESULTS: Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01). CONCLUSIONS: The estrogen SNP pathway was associated with POAG among women.

Trends in use of ancillary glaucoma tests for patients with open-angle glaucoma from 2001 to 2009.

PURPOSE: To assess trends in the use of ancillary diagnostic tests in the evaluation of patients with open-angle glaucoma (OAG) and glaucoma suspects over the past decade. DESIGN: Retrospective, longitudinal cohort analysis. PARTICIPANTS: A total of 169 917 individuals with OAG and 395 721 individuals with suspected glaucoma aged ≥40 years enrolled in a national United States managed care network between 2001 and 2009. METHODS: Claims data were analyzed to assess trends in visual field (VF) testing, fundus photography (FP), and other ocular imaging (OOI) testing for patients with OAG or suspected glaucoma between 2001 and 2009. Repeated-measures logistic regression was performed to identify differences in the odds of undergoing these procedures in 2001, 2005, and 2009 and whether differences exist for patients under the exclusive care of optometrists versus ophthalmologists. MAIN OUTCOME MEASURES: Odds and annual probabilities of undergoing VF testing, FP, and OOI for OAG from 2001 to 2009. RESULTS: For patients with OAG, the odds of undergoing VF testing decreased by 36% from 2001 to 2005, by 12% from 2005 to 2009, and by 44% from 2001 to 2009. By comparison, the odds of having OOI increased by 100% from 2001 to 2005, by 24% from 2005 to 2009, and by 147% from 2001 to 2009. Probabilities of undergoing FP were relatively low (13%-25%) for both provider types and remained fairly steady over the decade. For patients cared for exclusively by optometrists, the probability of VF testing decreased from 66% in 2001 to 44% in 2009. Among those seen exclusively by ophthalmologists, the probability of VF testing decreased from 65% in 2001 to 51% in 2009. The probability of undergoing OOI increased from 26% in 2001 to 47% in 2009 for patients of optometrists and from 30% in 2001 to 46% in 2009 for patients of ophthalmologists. By 2008, patients with OAG receiving care exclusively by optometrists had a higher probability of undergoing OOI than VF testing. CONCLUSIONS: From 2001 to 2009, OOI increased dramatically whereas VF testing declined considerably. Because OOI has not been shown to be as effective at detecting OAG or disease progression compared with VF testing, increased reliance on OOI technology, in lieu of VF testing, may be detrimental to patient care.

Intraocular pressure control and long-term visual field loss in the Collaborative Initial Glaucoma Treatment Study.

OBJECTIVE: To evaluate the impact of measures of intraocular pressure (IOP) control on progression of visual field (VF) loss during long-term treatment for open-angle glaucoma (OAG). DESIGN: Longitudinal, randomized clinical trial. PARTICIPANTS: We included 607 participants with newly diagnosed OAG. METHODS: Study participants were randomly assigned to initial treatment with medications or trabeculectomy, and underwent examination at 6-month intervals. Standardized testing included Goldmann applanation tonometry and Humphrey 24-2 full threshold VFs. Summary measures of IOP control during follow-up included the maximum, mean, standard deviation (SD), range, proportion less than 16, 18, 20, or 22 mmHg, and whether all IOP values were less than each of these 4 cutpoints. Predictive models for VF outcomes were based on the mean deviation (MD) from VF testing, and were adjusted for age, gender, race, baseline VF loss, treatment, and time. Each summary IOP measure was included as a cumulative, time-dependent variable, and its association with subsequent VF loss was assessed from 3 to 9 years postrandomization. Both linear mixed models, to detect shifts in MD levels, and logistic models, to detect elevated odds of substantial worsening (≥3 dB), were used. MAIN OUTCOME MEASURES: We measured the MD from Humphrey 24-2 full threshold VF tests. RESULTS: The effect of the summary IOP measures differed between the medicine and surgery groups in models that addressed the continuous MD outcome. After adjustment for baseline risk factors, in the medicine group larger values of 3 IOP control measures-maximum IOP (P = 0.0003), SD of IOP (P = 0.0056), and range of IOP (P<0.0001)-were significantly associated with lower (worse) MD over the 3- to 9-year period. No IOP summary measure was significantly associated with MD over time in the surgery group. The same 3 IOP summary measures were also significantly associated with substantial worsening of MD; however, the effects were similar in both treatment groups. In models predicting inadequate IOP control, consistently significant predictors of higher maximum, SD, and range of IOP included black race, higher baseline IOP, and clinical center. CONCLUSIONS: These results support considering more aggressive treatment when undue elevation or variation in IOP measures is observed.

Demographic, Comorbid, and Clinical Variables Associated With Pointwise Visual Field Damage in Glaucoma: Data From the AGIS and CIGTS Clinical Trials.

Purpose: To investigate differences across the visual field (VF) in the rate of glaucomatous progression, the likelihood of defect in four disease severity cross-sections, and comparisons of subgroups in each of between 12 demographic, comorbid, and clinical variables. Methods: Two long-term glaucoma clinical trials used Humphrey Field Analyzer 24-2 VFs to calculate pointwise deviations from age-matched normal controls. Slopes of glaucomatous progression over time were calculated per participant using linear mixed models. Pointwise differences between subgroups in slopes and cross-sectional categories were tested, adjusting for multiple comparisons using false discovery rate (FDR) and Q values. Results: Pointwise data were available for 1118 patients who had 15,073 VFs. On average, defects were seen at all VF points. Of the 12 variables, six had average pointwise slopes where Subgroup 1 had significantly faster progression than Subgroup 2 at all or many of the 52 VF points: participants who were older (≥65 vs. younger), 52/52; were male, 13/52; had diabetes, 29/52; had hypertension, 46/52; had a larger cup-to-disc ratio (≥0.7), 36/52; or had larger differences in absolute mean deviation (MD) between eyes (>3 dB), 52/52. Cross-sectional patterns at MD severity of -12 to -6.1 dB showed strong midline effects for gender and other patterns for hypertension, cup-to-disc ratio, absolute difference in MD between eyes, and disc notching. Conclusions: The approach used provides new longitudinal and cross-sectional insights into variation across the VF associated with demographic, comorbid, and clinical variables. Translational Relevance: This exploration and characterization of variable effects in the setting of pointwise VF testing may enable clinicians to anticipate patterns of VF loss based on demographic, comorbid, and clinical associations.

The Michigan Vision-Related Anxiety Questionnaire: A Psychosocial Outcomes Measure for Inherited Retinal Degenerations.

OBJECTIVE: We sought to construct and validate a patient-reported outcome measure for screening and monitoring vision-related anxiety in patients with inherited retinal degenerations. DESIGN: Item-response theory and graded response modeling to quantitatively validate questionnaire items generated from qualitative interviews and patient feedback. METHODS: Patients at the Kellogg Eye Center (University of Michigan, Ann Arbor, Michigan, USA) with a clinical diagnosis of an inherited retinal degeneration (n = 128) participated in an interviewer-administered questionnaire. The questionnaire consisted of 166 items, 26 of which pertained to concepts of "worry" and "anxiety." The subset of vision-related anxiety questions was analyzed by a graded response model using the Cai Metropolis-Hastings Robbins-Monro algorithm in the R software mirt package. Item reduction was performed based on item fit, item information, and item discriminability. To assess test-retest variability, 25 participants completed the questionnaire a second time 4 to 16 days later. RESULTS: The final questionnaire consisted of 14 items divided into 2 unidimensional domains: rod function anxiety and cone function anxiety. The questionnaire exhibited convergent validity with the Patient Health Questionnaire for symptoms of depression and anxiety. This vision-related anxiety questionnaire has high marginal reliability (0.81 for rod-function anxiety, 0.83 for cone-function anxiety) and exhibits minimal test-retest variability (ρ = 0.81 [0.64-0.91] for rod-function anxiety and ρ = 0.83 [0.68-0.92] for cone-function anxiety). CONCLUSIONS: The Michigan Vision-Related Anxiety Questionnaire is a psychometrically validated 14-item patient-reported outcome measure to be used as a psychosocial screening and monitoring tool for patients with inherited retinal degenerations. It can be used in therapeutic clinical trials for measuring the benefit of an investigational therapy on a patient's vision-related anxiety.

Visual field progression in the Collaborative Initial Glaucoma Treatment Study the impact of treatment and other baseline factors.

PURPOSE: To evaluate factors associated with visual field (VF) progression, using all available follow-up through 9 years after treatment initiation, in the Collaborative Initial Glaucoma Treatment Study (CIGTS). DESIGN: Longitudinal follow-up of participants enrolled in a randomized clinical trial. PARTICIPANTS: Six hundred seven newly diagnosed glaucoma patients. METHODS: In a randomized clinical trial, 607 subjects with newly diagnosed open-angle glaucoma initially were treated with either medication or trabeculectomy. After treatment initiation and early follow-up, subjects were evaluated clinically at 6-month intervals. Study participants in both arms of the CIGTS were treated aggressively in an effort to reduce intraocular pressure (IOP) to a level at or below a predetermined, eye-specific target pressure. Visual field progression was analyzed using repeated measures models. MAIN OUTCOME MEASURES: Visual field progression, measured by Humphrey 24-2 full-threshold testing and assessed by the change in the mean deviation (MD), and an indicator of substantial worsening of the VF (MD decrease of > or =3 dB from baseline), assessed at each follow-up visit. RESULTS: Follow-up indicated minimal change from baseline in each initial treatment group's average MD. However, at the 8-year follow-up examination, substantial worsening (> or =3 dB) of MD from baseline was found in 21.3% and 25.5% of the initial surgery and initial medicine groups, respectively. The effect of initial treatment on subsequent VF loss was modified by time (P<0.0001), baseline MD (P = 0.03), and diabetes (P = 0.01). Initial surgery led to less VF progression than initial medicine in subjects with advanced VF loss at baseline, whereas subjects with diabetes had more VF loss over time if treated initially with surgery. CONCLUSIONS: The CIGTS intervention protocol led to a lowering of IOP that persisted over time in both treatment groups. Progression in VF loss was seen in a subset, increasing to more than 20% of the subjects. The findings regarding initial surgery being beneficial for subjects with more advanced VF loss at presentation, but detrimental for patients with diabetes, are noteworthy and warrant independent confirmation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Characteristics of Industry Payments to Ophthalmologists in the Open Payments Database.

Importance: An increased awareness of the interactions between the medical industry and health care professionals may lead to lower health care costs and more effective health care practices. Objective: To assess the characteristics of industry payments made to ophthalmologists between 2013 and 2017. Design, Setting, and Participants: This analysis included data reported in the June 29, 2018, update of the Centers for Medicare & Medicaid Services Open Payments Database (OPD). The OPD contains public records of industry payments made to physicians and teaching hospitals from August 1, 2013, to December 31, 2017, as reported by the medical industry. All general or research payments distributed to US ophthalmologists and contained in the OPD were included in this study. Data are summarized by practitioner, manufacturer, payment category, and geographic location. Main Outcomes and Measures: Main outcomes were the distribution, quantity, and value of payments made to ophthalmologists practicing in the United States or US territories. The financial characteristics of payment category, manufacturer, product, and location were also assessed. Results: This analysis revealed that the OPD showed industry reporting a total of 20 943 ophthalmologists receiving 736 517 payments worth $543 679 603.53 (1.67% of all industry-reported funds in the OPD). The median payment value was $22.44. Most payments were for food and beverages (581 588 [78.96%]), whereas most funds were allocated toward research ($310 142 151.88 [57.05%]) and consulting fees ($73 565 327.71 [13.51%]). The median payout to each ophthalmologist was $637.75 (interquartile range, $167.33-$2065.54). California was the highest-grossing state, receiving $101 135 980.34 (18.60%) of all payments. Fifteen companies were responsible for 87.68% of all funds distributed ($476 719 470.11) and were mostly involved in the production of pharmaceutical agents (anti-vascular endothelial growth factor agents, glaucoma eyedrops, and ocular lubricants) and surgical devices (cataract and glaucoma). Conclusions and Relevance: Although there is no way to know the veracity of these reports, the findings suggest the financial ophthalmologist-industry relationship is substantial. These relationships may be adding to health care costs and affecting the quality of care, although those associations were not evaluated in this study.

Association of Mandatory Disclosure Policies and Laws With Physician-Industry Financial Relationships.

Importance: Beside the goal of increasing transparency to the public, disclosure policies and laws have been established with a goal to also reduce ethically questionable financial relationships between physicians and the medical industry. Data on these relationships should be reviewed to understand the association between these policies and laws and the attainment of reduced relationships. Objective: To assess whether disclosure policies and laws have been associated with a decrease in financial disclosure reporting by physicians. Design, Setting, and Participants: This cross-sectional study uses yearly data from 2008 through 2015 from the participants in the American Academy of Ophthalmology's Annual Meeting. Trends in financial disclosures over time were investigated for the association of disclosure policies and laws with potentially beneficial, as well as ethically questionable physician-industry ties. Linear regression models were used to estimate the annual change in financial disclosures and are reported with 95% CIs. Exposures: Disclosure policies and laws. Main Outcomes and Measures: The annual aggregate financial disclosures by type (ie, consultant, lecturer, employee, grant support, equity owner, patent holder). Results: Financial disclosures increased from 3966 in 2008 to 5266 in 2015 (P < .001). The number of disclosures reported in the categories consultant, equity owner, patents, and grant support all increased from 2008 to 2015 (consultant disclosures, 121 [95% CI, 88-155] per year; P < .001; equity owner disclosures, 32 [95% CI, 22-42] per year; P < .001; patent disclosures, 19 [95% CI, 13-26] per year; P < .001; grant support disclosures, 78 [95% CI, 48-107] per year; P < .001), while the employee and lecturer categories did not change significantly. The percentage of financial disclosures in the lecturer category decreased relative to the total (estimate, -1.1% [95% CI, -1.3% to -0.8%] per year; P < .001), owing to the number of financial disclosures for this category remaining stable while most other types increased. Conclusions and Relevance: Disclosure was not associated with a chilling effect (decrease in financial disclosures associated with potentially beneficial physician-industry ties). Disclosure was associated with a possible disinfecting effect, whereby the percentage of ethically questionable disclosures (ie, lecturers) decreased, although the frequency remained stable. A permissive effect (physicians becoming more inclined to having industry relationships) was also observed. Thus, disclosure rules should be enhanced or alternative approaches to disclosure reconsidered to promote a decrease in ethically questionable relationships.

Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis.

IMPORTANCE: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations. OBJECTIVE: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018. MAIN OUTCOMES AND MEASURES: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression. RESULTS: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (ß = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4). CONCLUSIONS AND RELEVANCE: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

Factors associated with intraocular pressure before and during 9 years of treatment in the Collaborative Initial Glaucoma Treatment Study.

PURPOSE: To evaluate, both at initial glaucoma diagnosis and during treatment, the role of demographic and clinical factors on intraocular pressure (IOP). DESIGN: Cohort study of patients enrolled in a randomized clinical trial. PARTICIPANTS: Six hundred seven patients with newly diagnosed open-angle glaucoma (OAG) were enrolled at 14 centers in the United States. METHODS: After randomization to initial surgery or medications, patients were followed at 6-month intervals. Intraocular pressure was measured by Goldmann applanation tonometry. Predictive factors for IOP at baseline and during follow-up were analyzed using linear mixed models. MAIN OUTCOME MEASURE: Intraocular pressure at baseline and during follow-up. RESULTS: The mean baseline IOP was 27.5 mmHg (standard deviation, 5.6 mmHg). Predictive factors for higher baseline IOP included younger age (0.7 mmHg per 10 years), male gender (2.4 mmHg higher than females), pseudoexfoliative glaucoma (5.4 mmHg higher than primary OAG), and pupillary defect (2.2 mmHg higher than those without a defect). During 9 years of follow-up, both surgery and medications dramatically reduced IOP from baseline levels, but the extent of IOP reduction was consistently greater in the surgery group. Over follow-up years 2 through 9, mean IOP was 15.0 versus 17.2 mmHg for surgery versus medicine, respectively. Predictive associations with higher IOP during follow-up included higher baseline IOP (P<0.0001), worse baseline visual field (mean deviation; P<0.0001), and lower level of education (P = 0.0019). Treatment effect was modified by smoking status: nonsmokers treated surgically had lower IOP than smokers treated surgically (14.6 vs. 16.7 mmHg, respectively; P = 0.0013). Clinical center effects were significant (P<0.0001) in both the baseline and follow-up models. CONCLUSIONS: In this large cohort of newly diagnosed glaucoma patients, predictors of pretreatment IOP and IOP measurements over 9 years of follow-up were identified. Our findings lend credence to the postulate that sociodemographic, economic, compliance, or other environmental influences play a role in IOP control during treatment.

Debunking myths in physician-industry conflicts of interest.

PURPOSE: To call attention to the myths that surround physician-industry conflicts of interest, to refute their validity, and to propose ways to address them so as to insure that physicians make medical practice decisions in the best interest of their patients. DESIGN: Perspective. METHODS: Review, analysis, and discussion of the implications of selected pertinent literature. RESULTS: Physicians often have voluntary financial relationships with industry based on behaviors and motivations that include entitlement, recognition, belonging, and money. The pharmaceutical and device industry spends billions of dollars annually in marketing to physicians. The sophisticated marketing plan seeks access to physicians through gifting mechanisms to ingratiate them and to influence them to prescribe industry's drugs and to purchase its products. Despite widely accepted studies that demonstrate that industry's marketing activities influence physicians' medical practice behavior to the detriment of patients and the public, physicians persist in voicing myths to justify their partaking of industry's largesse. Many physicians believe that their voluntary financial conflicts of interest with industry can be managed by simply disclosing them and by "being honest." Yet there is no support from well-conducted studies to support the effectiveness of this approach. CONCLUSIONS: Medical organizations and academic institutions are the ones to take the lead in recognizing that these voluntary financial conflicts of interest are unacceptable and should be stopped. Such conflicts mainly relate to the acceptance of gifts and money that are designed to influence behavior and are a form of financial coercion.