Examining Bias in Published Surgical Glaucoma Clinical Trials.

PRCIS: Our results demonstrate that, among randomized clinical trials examining the use of surgical treatments for glaucoma, the majority were not registered. Publication bias (PB) was less likely. More than a third of registered trials presented outcome reporting bias (ORB). PURPOSE: Despite the optimum of quality evidence provided by randomized controlled trials (RCTs), biases may be introduced and hinder their application. The primary objective of this study was to investigate ORB and PB in RCTs assessing surgical treatments of glaucoma, as well as their registration status. MATERIALS AND METHODS: A literature review was conducted in MEDLINE, EMBASE, and CENTRAL databases. Inclusion criteria were RCTs published in English between 2007 and 2021 that focused on surgical treatments of patients of all ages with glaucoma or elevated intraocular pressure. Exclusion criteria included cadaveric and animal studies. Registration status was correlated with entries from clinical trial registries. PB was determined by the proportion of trials presenting statistically significant results. ORB was evaluated by comparing the study's primary outcome with that listed in the trial registry. Trials quality was assessed using the Jadad score. RESULTS: After deleting duplicates, 7561 citations were screened. One hundred sixty-one RCTs were eligible and included between 13 and 556 participants. Of the total, 91% studied an adult population and 71% included patients suffering from primary open angle glaucoma. Among included studies, 63% were not registered and 47% had statistically significant results. An upward trend in registration was observed with time. However, 37% of the studies showed discrepancies between objectives in cited clinical trial registries and the published results. CONCLUSION: PB in surgical glaucoma trials was not obvious. Among the minority of trials that were registered, more than a third presented ORB. Unregistered trials had lower quality. RCT registration is crucial for the transparent interpretation of studies, improved patient care in surgery, and informed decision-making.

COVID-19 and the Rationale for Primary Selective Laser Trabeculoplasty and Diode Laser Transscleral Cyclophotocoagulation in Africa.

The recent COVID-19 pandemic has affected ophthalmologists' practices worldwide. Consequent global drug shortages and the limitations of medical glaucoma treatments in sub-Saharan Africa have highlighted the need for innovation in global ophthalmology to provide accessible, affordable, and effective glaucoma care. The role of lasers rather than medications for glaucoma patients in developing nations is emerging. Since lasers are easier to master than glaucoma surgery, it is pertinent to discuss the primary use of lasers in treating glaucoma in such nations. In particular, selective laser trabeculoplasty and diode laser transscleral cyclophotocoagulation seem to present a promising future for the treatment of glaucoma in Africa. In this report, we provide an evidence-based discussion exploring the emerging role of lasers in Africa.

Neural network and logistic regression diagnostic prediction models for giant cell arteritis: development and validation.

PURPOSE: To develop and validate neural network (NN) vs logistic regression (LR) diagnostic prediction models in patients with suspected giant cell arteritis (GCA). Design: Multicenter retrospective chart review. METHODS: An audit of consecutive patients undergoing temporal artery biopsy (TABx) for suspected GCA was conducted at 14 international medical centers. The outcome variable was biopsy-proven GCA. The predictor variables were age, gender, headache, clinical temporal artery abnormality, jaw claudication, vision loss, diplopia, erythrocyte sedimentation rate, C-reactive protein, and platelet level. The data were divided into three groups to train, validate, and test the models. The NN model with the lowest false-negative rate was chosen. Internal and external validations were performed. RESULTS: Of 1,833 patients who underwent TABx, there was complete information on 1,201 patients, 300 (25%) of whom had a positive TABx. On multivariable LR age, platelets, jaw claudication, vision loss, log C-reactive protein, log erythrocyte sedimentation rate, headache, and clinical temporal artery abnormality were statistically significant predictors of a positive TABx (P≤0.05). The area under the receiver operating characteristic curve/Hosmer-Lemeshow P for LR was 0.867 (95% CI, 0.794, 0.917)/0.119 vs NN 0.860 (95% CI, 0.786, 0.911)/0.805, with no statistically significant difference of the area under the curves (P=0.316). The misclassification rate/false-negative rate of LR was 20.6%/47.5% vs 18.1%/30.5% for NN. Missing data analysis did not change the results. CONCLUSION: Statistical models can aid in the triage of patients with suspected GCA. Misclassification remains a concern, but cutoff values for 95% and 99% sensitivities are provided (https://goo.gl/THCnuU).

Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.

CONTEXT: Selective eligibility criteria of randomized controlled trials (RCTs) are vital to trial feasibility and internal validity. However, the exclusion of certain patient populations may lead to impaired generalizability of results. OBJECTIVE: To determine the nature and extent of exclusion criteria among RCTs published in major medical journals and the contribution of exclusion criteria to the representation of certain patient populations. DATA SOURCES AND STUDY SELECTION: The MEDLINE database was searched for RCTs published between 1994 and 2006 in certain general medical journals with a high impact factor. Of 4827 articles, 283 were selected using a series technique. DATA EXTRACTION: Trial characteristics and the details regarding exclusions were extracted independently. All exclusion criteria were graded independently and in duplicate as either strongly justified, potentially justified, or poorly justified according to previously developed and pilot-tested guidelines. DATA SYNTHESIS: Common medical conditions formed the basis for exclusion in 81.3% of trials. Patients were excluded due to age in 72.1% of all trials (60.1% in pediatric populations and 38.5% in older adults). Individuals receiving commonly prescribed medications were excluded in 54.1% of trials. Conditions related to female sex were grounds for exclusion in 39.2% of trials. Of all exclusion criteria, only 47.2% were graded as strongly justified in the context of the specific RCT. Exclusion criteria were not reported in 12.0% of trials. Multivariable analyses revealed independent associations between the total number of exclusion criteria and drug intervention trials (risk ratio, 1.35; 95% confidence interval, 1.11-1.65; P = .003) and between the total number of exclusion criteria and multicenter trials (risk ratio, 1.26; 95% confidence interval, 1.06-1.52; P = .009). Industry-sponsored trials were more likely to exclude individuals due to concomitant medication use, medical comorbidities, and age. Drug intervention trials were more likely to exclude individuals due to concomitant medication use, medical comorbidities, female sex, and socioeconomic status. Among such trials, justification for exclusions related to concomitant medication use and comorbidities were more likely to be poorly justified. CONCLUSIONS: The RCTs published in major medical journals do not always clearly report exclusion criteria. Women, children, the elderly, and those with common medical conditions are frequently excluded from RCTs. Trials with multiple centers and those involving drug interventions are most likely to have extensive exclusions. Such exclusions may impair the generalizability of RCT results. These findings highlight a need for careful consideration and transparent reporting and justification of exclusion criteria in clinical trials.

Development of a predictive model for temporal artery biopsies.

OBJECTIVE: Temporal artery biopsy is a critical, relatively safe, and reliable test in the diagnosis of temporal arteritis. Yet, a clarification of the pre-test probabilities may provide clarity on which patients with suspected giant cell arteritis would benefit from this invasive diagnostic procedure. DESIGN: A prospective case series PARTICIPANTS: A consecutive case series of patients referred to the Ophthalmology service for temporal artery biopsy. METHODS: All subjects underwent standardized serum testing, and signs and symptoms assessment. Predictive models were created and evaluated. RESULTS: 119 patients were analyzed. This exploratory study found that a simple model including platelet count, erythrocyte sedimentation rate, and c-reactive protein was able to define a subset of patients with a pre-test probability of a positive biopsy of 0% or 100%. 40% (95% confidence interval 31%-49%) of patients fell into this category. CONCLUSIONS: Utilizing a simple clinically applicable predictive model of the pretest probability of a temporal artery biopsy in patients with suspected giant cell arteritis, up to 31%-49% of temporal artery biopsies may be avoided. This study was a single site exploratory study with data-driven thresholds - therefore these results need to be validated with an independent sample prior to clinical use.

Multivariable prediction model for suspected giant cell arteritis: development and validation.

PURPOSE: To develop and validate a diagnostic prediction model for patients with suspected giant cell arteritis (GCA). METHODS: A retrospective review of records of consecutive adult patients undergoing temporal artery biopsy (TABx) for suspected GCA was conducted at seven university centers. The pathologic diagnosis was considered the final diagnosis. The predictor variables were age, gender, new onset headache, clinical temporal artery abnormality, jaw claudication, ischemic vision loss (VL), diplopia, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet level. Multiple imputation was performed for missing data. Logistic regression was used to compare our models with the non-histologic American College of Rheumatology (ACR) GCA classification criteria. Internal validation was performed with 10-fold cross validation and bootstrap techniques. External validation was performed by geographic site. RESULTS: There were 530 complete TABx records: 397 were negative and 133 positive for GCA. Age, jaw claudication, VL, platelets, and log CRP were statistically significant predictors of positive TABx, whereas ESR, gender, headache, and temporal artery abnormality were not. The parsimonious model had a cross-validated bootstrap area under the receiver operating characteristic curve (AUROC) of 0.810 (95% CI =0.766-0.854), geographic external validation AUROC's in the range of 0.75-0.85, calibration pH-L of 0.812, sensitivity of 43.6%, and specificity of 95.2%, which outperformed the ACR criteria. CONCLUSION: Our prediction rule with calculator and nomogram aids in the triage of patients with suspected GCA and may decrease the need for TABx in select low-score at-risk subjects. However, misclassification remains a concern.

Clinical predictors of positive temporal artery biopsy.

OBJECTIVE: We investigated the ability of known clinical signs and symptoms, as well as common laboratory tests, to correctly predict a positive temporal artery biopsy. DESIGN: A prospective cohort study. PARTICIPANTS: Consecutive patients in a tertiary referral centre undergoing temporal artery biopsy. METHODS: Clinical information was collected using a predesigned questionnaire. Pathology results and laboratory information were collected from digital patient records. MAIN OUTCOME MEASURE: The predictive value of clinical signs, symptoms, and laboratory values of a positive temporal artery biopsy. RESULTS: Over a 3-year period, 259 patients were enrolled and 251 patients were analyzed. Sixty-one patients had a positive biopsy. Clinical features most predictive of a positive biopsy were jaw claudication (positive likelihood ratio [LR+] 2.31) and abnormal temporal artery pulse (LR+ 2.62). Receiver operating characteristic curves generated for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelets values showed an area under curve (AUC) value of 0.71, 0.75, and 0.76, respectively. The initiation of steroids decreased the diagnostic utility of the ESR, CRP, and platelets values (AUC = 0.58, 0.61, and 0.63, respectively). CONCLUSIONS: A variety of clinical signs and symptoms were observed in patients referred for a temporal artery biopsy. Clinical signs and symptoms were less accurate in predicting a positive biopsy than laboratory tests. No combination of clinical signs and symptoms tested was able to predict giant cell arteritis with the certainty necessary to justify or withhold long-term steroid therapy.

Incidence of discordant temporal artery biopsy in the diagnosis of giant cell arteritis.

OBJECTIVE: We investigated the rate of discordant biopsy results (i.e., 1 side negative, 1 side positive) in patients who underwent initial bilateral temporal artery biopsies for suspected giant cell arteritis (GCA). DESIGN: A cohort study. PARTICIPANTS: Consecutive patients undergoing temporal artery biopsy were enrolled. Of the 259 patients enrolled, 250 underwent initial bilateral temporal artery biopsies. METHODS: Positive biopsies were defined based on accepted histologic definitions. Healed arteritis was considered a positive result. Clinical information was collected for all patients using a questionnaire administered by an ophthalmologist. Pathology results, including biopsy length (as measured by the pathologist), and laboratory information (i.e., serum erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP] levels) were collected from digital patient records for statistical analysis. The main outcome was the rate of discordant biopsy in consecutive patients who underwent initial bilateral temporal artery biopsy. RESULTS: Giant cell arteritis was confirmed in 62 (24.2%) of the 250 patients, including 3 patients with biopsies recorded as healed arteritis. The rate of discordant biopsy was 4.4% with 11 unilaterally positive biopsies. There was no statistical difference between the length of the left- and right-sided biopsies in either the unilaterally or bilaterally positive groups (p = 0.13 and p = 0.79, respectively). The average maximum ESR value for the bilateral group (58.7 mm/h) was significantly higher than the average maximum ESR value for the unilateral group (30.7 mm/h, p = 0.03). The average maximum CRP value for the bilateral group was 59.2 mg/L and 28.6 mg/L for the unilateral group (p = 0.30). Discordance between the localization of symptoms and the side of positive biopsy occurred in 3 patients (i.e., 3 patients had left-sided symptoms only, yet a right-sided positive biopsy). CONCLUSIONS: The rate of discordant biopsies in patients who underwent initial bilateral temporal artery biopsies was considerable in our patient cohort. Given this reasonably high rate of discordance between sides, as well as the lack of correlation between side of positivity and laterality of presenting symptoms, we recommend initial bilateral temporal artery biopsies to enhance the diagnostic certainty of the disease.