A note on handling conditional missing values.

In medical research, some variables are conditionally defined on some levels of another variable, leading to conditional missing data. Imputation of this type of structural missing data is needed given inefficiency of listwise deletion inherent in regression modeling. Using some examples, we illustrate handling of conditional missing values using simple imputation procedures in etiologic and prediction research.

Causal diagrams for disease latency bias.

BACKGROUND: Disease latency is defined as the time from disease initiation to disease diagnosis. Disease latency bias (DLB) can arise in epidemiological studies that examine latent outcomes, since the exact timing of the disease inception is unknown and might occur before exposure initiation, potentially leading to bias. Although DLB can affect epidemiological studies that examine different types of chronic disease (e.g. Alzheimer's disease, cancer etc), the manner by which DLB can introduce bias into these studies has not been previously elucidated. Information on the specific types of bias, and their structure, that can arise secondary to DLB is critical for researchers, to enable better understanding and control for DLB. DEVELOPMENT: Here we describe four scenarios by which DLB can introduce bias (through different structures) into epidemiological studies that address latent outcomes, using directed acyclic graphs (DAGs). We also discuss potential strategies to better understand, examine and control for DLB in these studies. APPLICATION: Using causal diagrams, we show that disease latency bias can affect results of epidemiological studies through: (i) unmeasured confounding; (ii) reverse causality; (iii) selection bias; (iv) bias through a mediator. CONCLUSION: Disease latency bias is an important bias that can affect a number of epidemiological studies that address latent outcomes. Causal diagrams can assist researchers better identify and control for this bias.

Increased risk of pigmentary degeneration of the iris and pigmentary glaucoma with fluoroquinolone antibiotics.

PURPOSE: Fluoroquinolones are popular antibiotics used for a myriad of conditions including ocular procedures. Despite numerous case reports of acute pigmentary degeneration of the iris with fluoroquinolone use, a pharmacoepidemiological study has not been performed to examine and quantify this risk. DESIGN: Retrospective cohort study with a case-control analysis. PARTICIPANTS: A cohort of 1,231,881 new users of oral or topical moxifloxacin, levofloxacin, and azithromycin were followed to first diagnosis of pigmentary degeneration of the iris or pigmentary glaucoma. Four controls were selected for each case using density sampling, matching on age and calendar time. METHODS: Users of oral or topical moxifloxacin were compared to levofloxacin and azithromycin, a negative control drug from a separate class. MAIN OUTCOMES AND MEASURES: First incidence of pigmentary degeneration of the iris or pigmentary glaucoma. RESULTS: The cohort was comprised of 1,231,881 new users of topical or oral levofloxacin, moxifloxacin, or azithromycin. 542 cases of pigmentary degeneration of the iris and 460 cases of pigmentary glaucoma were identified. The incidence of iris pigmentary degeneration or pigmentary glaucoma for topical moxifloxacin was 10.2/1000 person years compared to 2.6/1000 person years for topical azithromycin. Current topical moxifloxacin users had the highest adjusted IRR for pigmentary degeneration of the iris (IRR = 6.81, [95%CI:2.00-23.18]) and pigmentary glaucoma (IRR = 4.07 [95%CI:1.42-11.62]) respectively. CONCLUSIONS: The study findings suggest that patients using topical moxifloxacin may have increased risk of developing pigmentary degeneration of the iris and pigmentary glaucoma although the absolute increase was low. Future studies are needed to confirm this association.

Immune-Related Adverse Events Associated with Atezolizumab: Insights from Real-World Pharmacovigilance Data.

The advancement of immuno-oncology has brought about a significant shift in cancer treatment methods, with antibody-based immune checkpoint inhibitors like atezolizumab leading the way in this regard. However, the use of this checkpoint blockade can result in immune-related adverse events due to increased T-cell activity. The full spectrum of these events is not yet completely understood. In this study, the United States FDA Adverse Event Reporting System (FAERS) was utilized to investigate immune-related adverse events linked with the use of atezolizumab. The study identified forty-nine immune-related adverse events that affected multiple organ systems, including cardiovascular, respiratory, hematologic, hepatic, renal, gastrointestinal, neurologic, musculoskeletal, dermatologic, endocrine, and systemic disorders. The strongest signals for relative risk occurred for immune-mediated encephalitis (RR = 93.443), autoimmune myocarditis (RR = 56.641), immune-mediated hepatitis (RR = 49.062), immune-mediated nephritis (RR = 40.947), and autoimmune arthritis (RR = 39.382). Despite the morbidity associated with these adverse events, emerging evidence suggests potential associations with improved survival outcomes. Overall, this report sheds light on the widespread immune-related adverse events that cause significant morbidity and mortality in patients with cancer being treated with atezolizumab and brings attention to them for the clinicians treating these patients.

Adverse Events of PD-1, PD-L1, CTLA-4, and LAG-3 Immune Checkpoint Inhibitors: An Analysis of the FDA Adverse Events Database.

This study aimed to identify the 25 most prevalent adverse events (AEs) associated with FDA-approved immune checkpoint inhibitors (ICIs)-specifically, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors-using data from the FDA Adverse Events Reporting System (FAERS), a publicly available repository of reported drug adverse events, and AERSMine, an open-access pharmacovigilance tool, to investigate these adverse events. For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab. PD-L1 inhibitors also frequently caused pyrexia, diarrhea, and fatigue, with interstitial lung disease and hypothyroidism showing a class effect, and drug-specific AEs such as hepatotoxicity and chills. CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia. Rare but significant AEs across all inhibitors included myocarditis and myasthenia gravis. This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer.

Medications for attention deficit hyperactivity disorder associated with increased risk of developing glaucoma.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) therapies including atomoxetine, methylphenidate, and amphetamines are some of the most prescribed medications in North America. Due to their sympathomimetic action, these drugs are contraindicated in patients with a history of angle closure glaucoma (ACG). This study aims to determine the risk of ACG and open angle glaucoma (OAG) among users of these treatments. METHODS: This is a retrospective cohort study with a case control analysis using the PharMetrics Plus Database (IQVIA, USA). We created a cohort of new users of atomoxetine, methylphenidate, and amphetamines and they were followed to the first diagnosis of (1) ACG or OAG; or (2) end of follow up. For each case, four age-matched controls were selected. A conditional logistic regression model was used to adjust for confounders and to calculate adjusted incidence-rate-ratios (aIRRs). RESULTS: A total of 240,257 new users of the ADHD medications were identified. The mean age was 45.0 ± 19.4 years and 55% of the cohort was female. Regular users of atomoxetine and amphetamines had a higher aIRR for developing ACG compared with non-users (aIRR = 2.55 95% CI [1.20-5.43] and 2.27 95% CI [1.42-3.63], respectively); while users of methylphenidate had a higher aIRR for developing OAG (aIRR = 1.23 95% CI [1.05-1.59]). CONCLUSIONS: Use of amphetamines and atomoxetine had a higher risk for ACG, while use of methylphenidate was associated with a higher risk for OAG. Given the prevalence of ADHD medication use (medically and recreationally), our current data on their associated risk of glaucoma have profound public health implications.

Ocular adverse events following CAR-T cell therapy: A pharmacovigilance study and systematic review.

The rise of immuno-oncology, including the use of chimeric antigen receptor T-cell (CAR-T) therapy is bringing in a new wave of cancer treatments, particularly in hematologic malignancies. However, data on their adverse events, particularly of the eye, is under-reported. To assess the ocular adverse events associated with the six FDA-approved CAR-T cell therapies, a disproportionality analysis utilizing the FAERS database was conducted from the first quarter of 2017 to the third quarter of 2023, as well as a systematic review of case reports of ocular events following CAR-T cell therapy up to December 20, 2023. A total of 53 ocular adverse events were identified from the FDAs FAERS database. The adverse events most frequently observed were mydriasis and xerophthalmia with tisagenlecleucel (Kymriah). The systematic review resulted in 8 case reports encompassing 19 patients which included a total of 27 events. This study demonstrates the importance of anticipation of potential ocular adverse events by ophthalmologists and oncologists as they can greatly contribute to morbidity in patients with cancer.

Multiple Sclerosis Risk Among Anti-tumor Necrosis Factor Alpha Users: A Methodological Review of Observational Studies Based on Real-world Data.

Epidemiologic studies on the risk of multiple sclerosis (MS) or demyelinating events associated with anti-tumor necrosis factor alpha (TNFα) use among patients with rheumatic diseases or inflammatory bowel diseases have shown conflicting results. Causal directed acyclic graphs (cDAGs) are useful tools for understanding the differing results and identifying the structure of potential contributing biases. Most of the available literature on cDAGs uses language that might be unfamiliar to clinicians. This article demonstrates how cDAGs can be used to determine whether there is a confounder, a mediator or collider-stratification bias and when to adjust for them appropriately. We also use a case study to show how to control for potential biases by drawing a cDAG depicting anti-TNFα use and its potential to contribute to MS onset. Finally, we describe potential biases that might have led to contradictory results in previous studies that examined the effect of anti-TNFα and MS, including confounding, confounding by contraindication, and bias due to measurement error. Clinicians and researchers should be cognizant of confounding, confounding by contraindication, and bias due to measurement error when reviewing future studies on the risk of MS or demyelinating events associated with anti-TNFα use. cDAGs are a useful tool for selecting variables and identifying the structure of different biases that can affect the validity of observational studies.

Risk of ocular adverse events with aromatase inhibitors.

OBJECTIVE: Aromatase inhibitors (AIs) are a class of medications used for adjuvant treatment of breast cancer. Recent case reports suggest that AIs may be associated with various ocular adverse events (AEs). This study evaluates the risk of ocular AEs in patients who take AIs. METHOD: Disproportionality analysis was performed using data from the U.S. Food and Drug Administration's Adverse Events Reporting System database from 2004 to 2022. All cases of vitreomacular traction, macular edema, retinal deposits, retinal artery occlusion, macular hole, retinal hemorrhage, uveitis, retinal tear, retinal detachment, dry eye disease, blepharitis, and optic neuropathy were searched for the 3 AIs anastrozole, letrozole, and exemestane. A search also was performed on trastuzumab as a control. Reported odds ratios (RORs) and corresponding 95% CIs were computed. RESULTS: We identified 322 ocular AEs of interest for the 3 AIs and 55 for trastuzumab. Anastrozole had the most AEs (n = 163) and was found to have strong associations with vitreomacular traction (ROR = 665; 95% CI, 352-1255), macular edema (ROR = 37; 95% CI, 25-54), retinal deposits (ROR = 11; 95% CI, 2-77), and uveitis (ROR = 6; 95% CI, 4-9). Letrozole had strong associations with retinal deposits (ROR = 8, 95% CI, 1-57) and retinal artery occlusion (ROR = 6; 95% CI, 3-11). Exemestane had a strong association with macular holes (ROR = 10; 95% CI, 3-30). CONCLUSION: Disproportionality analysis revealed an increased risk of ocular AEs with each of the AIs. This study calls for clinicians, especially oncologists and ophthalmologists, to be vigilant in patients who are on AI therapy, allowing them to provide prompt interventions to mitigate further ocular morbidities.

Use of Diuretics and Risk of Acute Angle Closure: A Case-Control Study.

PURPOSE: To examine the possible link between acute angle closure (AAC) with use of diuretics. METHODS: A nested case-control study (NCC) was conducted among a cohort of diuretic users using the PharMetrics Plus database from 2006 to 2020. Cases were identified as the first international classification of diseases 9th and 10th editions (ICD-9/10) code for ACC. For each case, 4 controls were selected and matched to the cases by age and sex using density-based sampling. A conditional logistic regression model was used to compute rate ratios (RRs) adjusted for the drugs topiramate, bupropion, sulphonamide antibiotics, acetazolamide, and sulfasalazine. The RRs for a negative control drug, amlodipine, was also assessed. RESULTS: From the initial cohort of 713 574 diuretics users, 1 553 cases and 6 212 controls were identified. No increase in the risk of AAC with current users of diuretics was found (RR = 1.06, (95% CI: 0.81-1.37) for all diuretics; RR = 0.97, (95% CI: 0.71-1.32) for thiazides; RR = 1.24, (95% CI: 0.90-1.73) for loop diuretics; RR = 0.99, (95% CI: 0.73-1.36) for potassium sparing). CONCLUSION: We found no increase in the risk of acute angle closure with use of diuretics. Future studies are needed to confirm these findings.

The effect of smoking on latent hazard classes of metabolic syndrome using latent class causal analysis method in the Iranian population.

BACKGROUND: The prevalence of metabolic syndrome is increasing worldwide. Clinical guidelines consider metabolic syndrome as an all or none medical condition. One proposed method for classifying metabolic syndrome is latent class analysis (LCA). One approach to causal inference in LCA is using propensity score (PS) methods. The aim of this study was to investigate the causal effect of smoking on latent hazard classes of metabolic syndrome using the method of latent class causal analysis. METHODS: In this study, we used data from the Tehran Lipid and Glucose Cohort Study (TLGS). 4857 participants aged over 20 years with complete information on exposure (smoking) and confounders in the third phase (2005-2008) were included. Metabolic syndrome was evaluated as outcome and latent variable in LCA in the data of the fifth phase (2014-2015). The step-by-step procedure for conducting causal inference in LCA included: (1) PS estimation and evaluation of overlap, (2) calculation of inverse probability-of-treatment weighting (IPTW), (3) PS matching, (4) evaluating balance of confounding variables between exposure groups, and (5) conducting LCA using the weighted or matched data set. RESULTS: Based on the results of IPTW which compared the low, medium and high risk classes of metabolic syndrome (compared to a class without metabolic syndrome), no association was found between smoking and the metabolic syndrome latent classes. PS matching which compared low and moderate risk classes compared to class without metabolic syndrome, showed that smoking increases the probability of being in the low-risk class of metabolic syndrome (OR: 2.19; 95% CI: 1.32, 3.63). In the unadjusted analysis, smoking increased the chances of being in the low-risk (OR: 1.45; 95% CI: 1.01, 2.08) and moderate-risk (OR: 1.68; 95% CI: 1.18, 2.40) classes of metabolic syndrome compared to the class without metabolic syndrome. CONCLUSIONS: Based on the results, the causal effect of smoking on latent hazard classes of metabolic syndrome can be different based on the type of PS method. In adjusted analysis, no relationship was observed between smoking and moderate-risk and high-risk classes of metabolic syndrome.

Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss.

This database study examines the association between glucagon-like peptide 1 agonists (eg, semaglutide, liraglutide) used for weight loss and reports of gastrointestinal adverse events.

Effect of alcohol consumption on breast cancer: probabilistic bias analysis for adjustment of exposure misclassification bias and confounders.

PURPOSE: This study was conducted to evaluate the effect of alcohol consumption on breast cancer, adjusting for alcohol consumption misclassification bias and confounders. METHODS: This was a case-control study of 932 women with breast cancer and 1000 healthy control. Using probabilistic bias analysis method, the association between alcohol consumption and breast cancer was adjusted for the misclassification bias of alcohol consumption as well as a minimally sufficient set of adjustment of confounders derived from a causal directed acyclic graph. Population attributable fraction was estimated using the Miettinen's Formula. RESULTS: Based on the conventional logistic regression model, the odds ratio estimate between alcohol consumption and breast cancer was 1.05 (95% CI: 0.57, 1.91). However, the adjusted estimates of odds ratio based on the probabilistic bias analysis ranged from 1.82 to 2.29 for non-differential and from 1.93 to 5.67 for differential misclassification. Population attributable fraction ranged from 1.51 to 2.57% using non-differential bias analysis and 1.54-3.56% based on differential bias analysis. CONCLUSION: A marked measurement error was in self-reported alcohol consumption so after correcting misclassification bias, no evidence against independence between alcohol consumption and breast cancer changed to a substantial positive association.

Impact of the use of anti-glaucoma medications on the risk of herpetic keratitis recurrence.

PURPOSE: Numerous case reports have associated anti-glaucoma medications with recurrence of herpes simplex virus (HSV) and herpes zoster virus (HZV) keratitis. The aim of our study was to determine whether different anti-glaucoma agents are associated with recurrence of herpetic keratitis. METHODS: This was a retrospective cohort study using health databases from a Canadian province from January 2001 to December 2012. A new cohort of users on topical prostaglandins (PGs), beta blockers (BBs), alpha-2 agonists (AAs) and carbonic anhydrase inhibitors (CAIs) was created. The date of the third anti-glaucoma drug dispensation within 90 days was deemed the index date of the case. Herpetic keratitis events, as defined by an ICD-9/10 code for HSV or HZV keratitis, or the dispensation of an anti-viral medication by either an ophthalmologist or an optometrist, were examined prior to and following the index date. Risk ratios (RRs) were computed to compare the risk of HSV/HZV keratitis among the PG, BB, AA, and CAI groups individually and collectively while adjusting for age and sex. RESULTS: Among 19,986 users of glaucoma medications identified, there were 684 cases of HSV/HZV keratitis. There was no increased risk of HSV/HZV keratitis recurrence for any of the four glaucoma medications classes individually or collectively when adjusted for age and sex. There was also no increased risk for redeveloping either HSV keratitis only or HZV keratitis only amongst all anti-glaucoma users. CONCLUSION: There is no association between the use of topical ocular hypotensive therapies and HSV/HZV keratitis recurrence. Further studies are needed to confirm these findings.

Risk of Multiple Sclerosis Among Users of Antitumor Necrosis Factor α in 4 Canadian Provinces: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Antitumor necrosis factor α (TNFα) agents are a class of biologic drugs used for the treatment of several immune-mediated conditions. An increased risk of multiple sclerosis (MS) with their use has been suggested, but studies have been limited. Relevant population-based epidemiologic data linking anti-TNFα to MS are scarce. The objective was to compare the risk of MS in anti-TNFα users with nonusers among patients with rheumatic disease (RD) or inflammatory bowel disease (IBD). METHODS: A nested case-control study was conducted. Population-based health care-linked databases from 4 Canadian provinces were used. All patients with RD or IBD residing within a participating province between January 2000 and March 2018 were identified by validated case definitions. Any anti-TNFα dispensation in the 2 years before the index date (MS onset) was identified. Incident onset MS cases were ascertained using a validated algorithm. Up to 5 controls were matched to each MS case based on birth year ±3 years, disease duration, and health authority (based on region of residence). Conditional logistic regressions were used to calculate the incidence rate ratio (IRR) after adjusting for potential confounders. A meta-analysis was conducted to provide pooled estimates across provinces using random-effects models. RESULTS: Among 296,918 patients with RD patients, 462 MS cases (80.1% female, mean [SD] age, 47.4 [14.6] years) were matched with 2,296 controls (59.5% female, mean [SD] age, 47.4 [14.5] years). Exposure to anti-TNFα occurred in 18 MS cases and 42 controls. After adjusting for matching variables, sex, and the Charlson Comorbidity Index, the pooled IRR was 2.05 (95% CI, 1.13-3.72). Among 84,458 patients with IBD, 190 MS cases (69.5% female, mean [SD] age, 44.3 [12.3] years) were matched with 943 controls (54.1% female, mean [SD] age, 44.2 [12.2] years). Exposure to anti-TNFα occurred in 23 MS cases and 98 controls. The pooled adjusted IRR was 1.35 (95% CI, 0.70-2.59). DISCUSSION: The use of anti-TNFα was associated with an increased risk of MS compared with nonusers, especially among patients with RD. These findings could help clinicians and patients with RD to make more informed treatment decisions. Further studies are needed to validate these results for patients with IBD.