Comparators in Pharmacovigilance: A Quasi-Quantification Bias Analysis.

BACKGROUND AND OBJECTIVE: It is unclear which comparator is the most appropriate for bias reduction in disproportionality analyses based on spontaneous reports. We conducted a quasi-quantitative bias analysis using two well-studied drug-event combinations to assess how different comparators influence the directionality of bias in pharmacovigilance. METHODS: We used the US Food and Drug Administration Adverse Event Reporting System focusing on two drug-event combinations with a propensity for stimulated reporting: rivaroxaban and hepatotoxicity, and canagliflozin and acute kidney injury. We assessed the directionality of three disproportionality analysis estimates (reporting odds ratio, proportional reporting ratio, information component) using one unrestricted comparator (full data) and two restricted comparators (active comparator, active comparator with class exclusion). Analyses were conducted within two calendar time periods, defined based on external events (approval of direct oral anticoagulants, Food and Drug Administration safety warning on acute kidney injury with sodium-glucose cotransporter 2 inhibitors) hypothesized to alter reporting rates. RESULTS: There were no false-positive signals for rivaroxaban and hepatotoxicity irrespective of the comparator. Restricting to the initial post-approval period led to false-positive signals, with restricted comparators performing worse. There were false-positive signals for canagliflozin and acute kidney injury, with restricted comparators performing better. Restricting to the period before the Food and Drug Administration warning weakened the false-positive signal for canagliflozin and acute kidney injury across comparators. CONCLUSIONS: We could not identify a consistent and predictable pattern to the directionality of disproportionality analysis estimates with specific comparators. Calendar time-based restrictions anchored on relevant external events had a considerable impact.

Serological markers and long COVID-A rapid systematic review.

BACKGROUND: Long COVID is highly heterogeneous, often debilitating, and may last for years after infection. The aetiology of long COVID remains uncertain. Examination of potential serological markers of long COVID, accounting for clinical covariates, may yield emergent pathophysiological insights. METHODS: In adherence to PRISMA guidelines, we carried out a rapid review of the literature. We searched Medline and Embase for primary observational studies that compared IgG response in individuals who experienced COVID-19 symptoms persisting ≥12 weeks post-infection with those who did not. We examined relationships between serological markers and long COVID status and investigated sources of inter-study variability, such as severity of acute illness, long COVID symptoms assessed and target antigen(s). RESULTS: Of 8018 unique records, we identified 29 as being eligible for inclusion in synthesis. Definitions of long COVID varied. In studies that reported anti-nucleocapsid (N) IgG (n = 10 studies; n = 989 participants in aggregate), full or partial anti-Spike IgG (i.e. the whole trimer, S1 or S2 subgroups, or receptor binding domain, n = 19 studies; n = 2606 participants), or neutralizing response (n = 7 studies; n = 1123 participants), we did not find strong evidence to support any difference in serological markers between groups with and without persisting symptoms. However, most studies did not account for severity or level of care required during acute illness, and other potential confounders. CONCLUSIONS: Pooling of studies would enable more robust exploration of clinical and serological predictors among diverse populations. However, substantial inter-study variations hamper comparability. Standardized reporting practices would improve the quality, consistency and comprehension of study findings.

Myocarditis and Pericarditis Post-mRNA COVID-19 Vaccination: Insights from a Pharmacovigilance Perspective.

Concerns remain regarding the rare cardiovascular adverse events, myocarditis and pericarditis (myo/pericarditis), particularly in younger individuals following mRNA COVID-19 vaccination. Our study aimed to comprehensively assess potential safety signals related to these cardiac events following the primary and booster doses, with a specific focus on younger populations, including children as young as 6 months of age. Using the Vaccine Adverse Events Reporting System (VAERS), the United States national passive surveillance system, we conducted a retrospective pharmacovigilance study analyzing spontaneous reports of myo/pericarditis. We employed both frequentist and Bayesian methods and conducted subgroup analyses by age, sex, and vaccine dose. We observed a higher reporting rate of myo/pericarditis following the primary vaccine series, particularly in males and mainly after the second dose. However, booster doses demonstrated a lower number of reported cases, with no significant signals detected after the fourth or fifth doses. In children and young adults, we observed notable age and sex differences in the reporting of myo/pericarditis cases. Males in the 12-17 and 18-24-year-old age groups had the highest number of cases, with significant signals for both males and females after the second dose. We also identified an increased reporting for a spectrum of cardiovascular symptoms such as chest pain and dyspnea, which increased with age, and were reported more frequently than myo/pericarditis. The present study identified signals of myo/pericarditis and related cardiovascular symptoms after mRNA COVID-19 vaccination, especially among children and adolescents. These findings underline the importance for continued vaccine surveillance and the need for further studies to confirm these results and to determine their clinical implications in public health decision-making, especially for younger populations.

Pregnancy, fetal, and neonatal outcomes after a first booster dose of covid-19 vaccine during pregnancy in Ontario, Canada: population based, retrospective cohort study.

Objective: To assess risk of adverse pregnancy, fetal, and neonatal outcomes after a third dose (first booster dose) of covid-19 vaccine during pregnancy among individuals who had completed both doses of primary covid-19 vaccine series before pregnancy. Design: Population based, retrospective cohort study. Setting: Ontario, Canada, from 20 December 2021 to 31 August 2022. Participants: Individuals were included if they were pregnant with an expected date of delivery from 20 December 2021 (start date of third dose eligibility for everyone ≥18 years) to 31 August 2022, who had completed the two doses of primary covid-19 messenger RNA vaccine series before pregnancy, and became eligible for a third dose (≥six months since dose two) before the end of pregnancy. Main outcome measures: Pregnancy outcomes included hypertensive disorders of pregnancy, placental abruption, caesarean delivery, chorioamnionitis, and postpartum hemorrhage. Fetal and neonatal outcomes included stillbirth, preterm birth, admission to neonatal intensive care unit for >24 h, newborn 5 min Apgar score <7, and small-for-gestational age infant (<10th percentile). We estimated hazard ratios and 95% confidence intervals for study outcomes, treating dose three as a time varying exposure and adjusting for confounding using inverse probability weighting. Results: Among 32 689 births, 18 491 (56.6%) were born to individuals who received a third covid-19 dose during pregnancy. Compared with eligible individuals who did not receive a third dose during pregnancy, no increased risks were associated with receiving a third covid-19 vaccine dose during pregnancy for placental abruption (adjusted hazard ratio 0.84 (95% confidence interval 0.70 to 1.02)), chorioamnionitis (0.67 (0.49 to 0.90)), postpartum haemorrhage (1.01 (0.89 to 1.16)), caesarean delivery (0.90 (0.87 to 0.94)), stillbirth (0.56 (0.39 to 0.81)), preterm birth (0.91 (0.84 to 0.99)), neonatal intensive care unit admission (0.96 (0.90 to 1.03)), 5 min Apgar score<7 (0.96 (0.82 to 1.14)), or small-for-gestational age infant (0.86 (0.79 to 0.93)). Conclusion: Receipt of a third covid-19 vaccine dose during pregnancy was not associated with an increased risk of adverse pregnancy, fetal, or neonatal outcomes. These findings can help to inform evidence based decision making about the risks and benefits of covid-19 booster doses during pregnancy.

Risk of myocarditis and pericarditis in mRNA COVID-19-vaccinated and unvaccinated populations: a systematic review and meta-analysis.

OBJECTIVE: To summarise the available evidence on the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccination, compared with the risk among unvaccinated individuals in the absence of COVID-19 infection. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic databases (Medline, Embase, Web of Science and WHO Global Literature on Coronavirus Disease), preprint repositories (medRxiv and bioRxiv), reference lists and grey literature were searched from 1 December 2020 until 31 October 2022. STUDY SELECTION: Epidemiological studies of individuals of any age who received at least one dose of an mRNA COVID-19 vaccine, reported a risk of myo/pericarditis and compared the risk of myo/pericarditis to individuals who did not receive any dose of an mRNA COVID-19 vaccine. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently conducted screening and data extraction. The rate of myo/pericarditis among vaccinated and unvaccinated groups was recorded, and the rate ratios were calculated. Additionally, the total number of individuals, case ascertainment criteria, percentage of males and history of SARS-CoV-2 infection were extracted for each study. Meta-analysis was done using a random-effects model. RESULTS: Seven studies met the inclusion criteria, of which six were included in the quantitative synthesis. Our meta-analysis indicates that within 30-day follow-up period, vaccinated individuals were twice as likely to develop myo/pericarditis in the absence of SARS-CoV-2 infection compared to unvaccinated individuals, with a rate ratio of 2.05 (95% CI 1.49-2.82). CONCLUSION: Although the absolute number of observed myo/pericarditis cases remains quite low, a higher risk was detected in those who received mRNA COVID-19 vaccinations compared with unvaccinated individuals in the absence of SARS-CoV-2 infection. Given the effectiveness of mRNA COVID-19 vaccines in preventing severe illnesses, hospitalisations and deaths, future research should focus on accurately determining the rates of myo/pericarditis linked to mRNA COVID-19 vaccines, understanding the biological mechanisms behind these rare cardiac events and identifying those most at risk.

Temporal trends and determinants of COVID-19 vaccine series initiation after recent pregnancy.

During the rapid deployment of COVID-19 vaccines in 2021, safety concerns may have led some pregnant individuals to postpone vaccination until after giving birth. This study aimed to describe temporal patterns and factors associated with COVID-19 vaccine series initiation after recent pregnancy in Ontario, Canada. Using the provincial birth registry linked with the COVID-19 vaccine database, we identified all individuals who gave birth between January 1 and December 31, 2021, and had not yet been vaccinated by the end of pregnancy, and followed them to June 30, 2022 (follow-up ranged from 6 to 18 months). We used cumulative incidence curves to describe COVID-19 vaccine initiation after pregnancy and assessed associations with sociodemographic, pregnancy-related, and health behavioral factors using Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). Among 137,198 individuals who gave birth in 2021, 87,376 (63.7%) remained unvaccinated at the end of pregnancy; of these, 65.0% initiated COVID-19 vaccination by June 30, 2022. Lower maternal age (<25 vs. 30-34 y aHR: 0.73, 95%CI: 0.70-0.77), smoking during pregnancy (vs. nonsmoking aHR: 0.68, 95%CI: 0.65-0.72), lower neighborhood income (lowest quintile vs. highest aHR: 0.79, 95%CI: 0.76-0.83), higher material deprivation (highest quintile vs. lowest aHR: 0.74, 95%CI: 0.70-0.79), and exclusive breastfeeding (vs. other feeding aHR: 0.81, 95%CI: 0.79-0.84) were associated with lower likelihood of vaccine initiation. Among unvaccinated individuals who gave birth in 2021, COVID-19 vaccine initiation after pregnancy reached 65% by June 30, 2022, suggesting persistent issues with vaccine hesitancy and/or access to vaccination in this population.

Considerations on the use of different comparators in pharmacovigilance: A methodological review.

Pharmacovigilance studies based on spontaneous reporting systems use disproportionality analysis methods to identify drug-event combinations with higher-than-expected reporting. Enhanced reporting is deemed as a proxy for a detected signal and is used to generate drug safety hypotheses, which can then be tested in pharmacoepidemiologic studies or randomized controlled trials. Higher-than-expected reporting means that the reporting rate of a drug-event combination of interest is disproportionately higher than the rate in a specific comparator or reference set. Currently, it is unclear which comparator is the most appropriate for use in pharmacovigilance. Moreover, it is also unclear how the selection of a comparator may affect the directionality of the various reporting and other biases. This paper reviews commonly used comparators chosen for signal detection studies (active comparator, class-exclusion comparator, and full data reference set). We give an overview of the advantages and disadvantages of each method based on examples from the literature. We also touch upon the challenges related to the derivation of general recommendations for the selection of comparators when mining spontaneous reports for pharmacovigilance.

Concomitant use of statins and sodium-glucose co-transporter 2 inhibitors and the risk of myotoxicity reporting: A disproportionality analysis.

AIMS: Recent case reports have suggested that sodium-glucose co-transporter 2 (SGLT2) inhibitors may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins. METHODS: We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2 inhibitors, statins or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2 inhibitors and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0) and an extension of the proportional reporting ratio (PRR) (two-criteria set, safety signal if both criteria are met), using the full FAERS dataset as the reference set. In sensitivity analyses, we focussed on specific SGLT2 inhibitor-statin pairs with higher interaction potential (canagliflozin-rosuvastatin, empagliflozin-rosuvastatin) and accounted for stimulated reporting. RESULTS: There were 456 myopathy and 77 rhabdomyolysis reports involving both an SGLT2 inhibitor and a statin. Concomitant use of SGLT2 inhibitors and statins was not associated with an increased risk of myopathy (ROR 0.79, 95% CI 0.70 to 0.89) or rhabdomyolysis (ROR 0.58, 95% CI 0.41 to 0.83) reporting. For both outcomes, the Ω shrinkage measure was negative and only one criterion of the PRR extension was met. SGLT2 inhibitor-statin pairs with higher interaction potential yielded potential signals for rhabdomyolysis; these signals disappeared after accounting for stimulated reporting. CONCLUSION: There was no increased risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins or for specific drug pairs.

Temporal trends and determinants of COVID-19 vaccine coverage and series initiation during pregnancy in Ontario, Canada, December 2020 to December 2021: A population-based retrospective cohort study.

BACKGROUND: Population-based COVID-19 vaccine coverage estimates among pregnant individuals are limited. We assessed temporal patterns in vaccine coverage (≥1 dose before or during pregnancy) and evaluated factors associated with vaccine series initiation (receiving dose 1 during pregnancy) in Ontario, Canada. METHODS: We linked the provincial birth registry with COVID-19 vaccination records from December 14, 2020 to December 31, 2021 and assessed coverage rates among all pregnant individuals by month, age, and neighborhood sociodemographic characteristics. Among individuals who gave birth since April 2021-when pregnant people were prioritized for vaccination-we assessed associations between sociodemographic, behavioral, and pregnancy-related factors with vaccine series initiation using multivariable regression to estimate adjusted risk ratios (aRR) and risk differences (aRD) with 95% confidence intervals (CI). RESULTS: Among 221,190 pregnant individuals, vaccine coverage increased to 71.2% by December 2021. Gaps in coverage across categories of age and sociodemographic characteristics decreased over time, but did not disappear. Lower vaccine series initiation was associated with lower age (<25 vs. 30-34 years: aRR 0.53, 95%CI 0.51-0.56), smoking (vs. non-smoking: 0.64, 0.61-0.67), no first trimester prenatal care visit (vs. visit: 0.80, 0.77-0.84), and residing in neighborhoods with the lowest income (vs. highest: 0.69, 0.67-0.71). Vaccine series initiation was marginally higher among individuals with pre-existing medical conditions (vs. no conditions: 1.07, 1.04-1.10). CONCLUSIONS: COVID-19 vaccine coverage among pregnant individuals remained lower than in the general population, and there was lower vaccine initiation by multiple characteristics.

Risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy: population based retrospective cohort study.

OBJECTIVE: To assess the risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy. DESIGN: Population based retrospective cohort study. SETTING: Ontario, Canada, 1 May to 31 December 2021. PARTICIPANTS: All liveborn and stillborn infants from pregnancies conceived at least 42 weeks before the end of the study period and with gestational age ≥20 weeks or birth weight ≥500 g. MAIN OUTCOME MEASURES: Using Cox regression, hazard ratios and 95% confidence intervals were estimated for preterm birth before 37 weeks (overall and spontaneous preterm birth), very preterm birth (<32 weeks), small for gestational age at birth (<10th centile), and stillbirth. Vaccination against covid-19 was treated as a time varying exposure in the outcome specific risk window, and propensity score weighting was used to adjust hazard ratios for potential confounding. RESULTS: Among 85 162 births, 43 099 (50.6%) occurred in individuals who received one dose or more of a covid-19 vaccine during pregnancy-42 979 (99.7%) received an mRNA vaccine. Vaccination during pregnancy was not associated with any increased risk of overall preterm birth (6.5% among vaccinated v 6.9% among unvaccinated; adjusted hazard ratio 1.02, 95% confidence interval 0.96 to 1.08), spontaneous preterm birth (3.7% v 4.4%; 0.96, 0.90 to 1.03), or very preterm birth (0.59% v 0.89%; 0.80, 0.67 to 0.95). No increase was found in risk of small for gestational age at birth (9.1% v 9.2%; 0.98, 0.93 to 1.03) or stillbirth (0.25% v 0.44%; 0.65, 0.51 to 0.84). Findings were similar by trimester of vaccination, mRNA vaccine product, and number of doses received during pregnancy. CONCLUSION: The findings suggest that vaccination against covid-19 during pregnancy is not associated with a higher risk of preterm birth, small for gestational age at birth, or stillbirth.

Risk of Myocarditis and Pericarditis among Young Adults following mRNA COVID-19 Vaccinations.

There have been reports of cases of myocarditis and pericarditis as rare complications following mRNA COVID-19 vaccinations among young adults. While most reported cases are mild, this potential vaccine safety signal should be closely monitored. Using data from the CDC and the Vaccine Adverse Event Reporting System (VAERS), we calculated the combined reporting rate of myocarditis and pericarditis stratified by age group, sex, vaccine dose, and manufacturer, and compared these rates to the crude background incidence rates. Compared to the general population prior to the administration of the first COVID-19 vaccines in December 2020, we identified a higher-than-expected reporting rate of myocarditis and pericarditis following mRNA vaccination; the risk was higher after a second vaccine dose, higher in males than in females, and decreased with age. The highest risk was seen in males 12-17 years of age with approximately 6 cases per 100,000 second doses. Our findings suggest an increased risk of myocarditis and pericarditis in young males following a second dose of an mRNA COVID-19 vaccine. Since these findings are based on safety signals derived from passive surveillance data, confirmatory epidemiological studies should be undertaken.

Association of COVID-19 Vaccination in Pregnancy With Adverse Peripartum Outcomes.

Importance: There is limited comparative epidemiological evidence on outcomes associated with COVID-19 vaccination during pregnancy; monitoring pregnancy outcomes in large populations is required. Objective: To evaluate peripartum outcomes following COVID-19 vaccination during pregnancy. Design, Setting, and Participants: Population-based retrospective cohort study in Ontario, Canada, using a birth registry linked with the provincial COVID-19 immunization database. All births between December 14, 2020, and September 30, 2021, were included. Exposures: COVID-19 vaccination during pregnancy, COVID-19 vaccination after pregnancy, and no vaccination. Main Outcomes and Measures: Postpartum hemorrhage, chorioamnionitis, cesarean delivery (overall and emergency cesarean delivery), admission to neonatal intensive care unit (NICU), and low newborn 5-minute Apgar score (<7). Linear and robust Poisson regression was used to generate adjusted risk differences (aRDs) and risk ratios (aRRs), respectively, comparing cumulative incidence of outcomes in those who received COVID-19 vaccination during pregnancy with those vaccinated after pregnancy and those with no record of COVID-19 vaccination at any point. Inverse probability of treatment weights were used to adjust for confounding. Results: Among 97 590 individuals (mean [SD] age, 31.9 [4.9] years), 22 660 (23%) received at least 1 dose of COVID-19 vaccine during pregnancy (63.6% received dose 1 in the third trimester; 99.8% received an mRNA vaccine). Comparing those vaccinated during vs after pregnancy (n = 44 815), there were no significantly increased risks of postpartum hemorrhage (incidence: 3.0% vs 3.0%; aRD, -0.28 per 100 individuals [95% CI, -0.59 to 0.03]; aRR, 0.91 [95% CI, 0.82-1.02]), chorioamnionitis (0.5% vs 0.5%; aRD, -0.04 per 100 individuals [95% CI, -0.17 to 0.09]; aRR, 0.92 [95% CI, 0.70-1.21]), cesarean delivery (30.8% vs 32.2%; aRD, -2.73 per 100 individuals [95% CI, -3.59 to -1.88]; aRR, 0.92 [95% CI, 0.89-0.95]), NICU admission (11.0% vs 13.3%; aRD, -1.89 per 100 newborns [95% CI, -2.49 to -1.30]; aRR, 0.85 [95% CI, 0.80-0.90]), or low Apgar score (1.8% vs 2.0%; aRD, -0.31 per 100 newborns [95% CI, -0.56 to -0.06]; aRR, 0.84 [95% CI, 0.73-0.97]). Findings were qualitatively similar when compared with individuals who did not receive COVID-19 vaccination at any point (n = 30 115). Conclusions and Relevance: In this population-based cohort study in Ontario, Canada, COVID-19 vaccination during pregnancy, compared with vaccination after pregnancy and with no vaccination, was not significantly associated with increased risk of adverse peripartum outcomes. Study interpretation should consider that the vaccinations received during pregnancy were primarily mRNA vaccines administered in the second and third trimester.

Systemic quinolones and risk of retinal detachment I: analysis of data from the US FDA adverse event reporting system.

BACKGROUND: Quinolones comprise a class of antibiotics that are globally preferred for treating a wide range of bacterial infections due to their potency, broad coverage, favorable pharmacologic profile, and mostly mild to moderate adverse reactions. Spontaneous reports on adverse drug events (ADE) and data from some pharmacoepidemiologic studies have raised concerns regarding quinolones and risk of retinal detachment (RD). This study examined ADE reports submitted to FDA adverse event reporting system (FAERS) for evidence on quinolone-associated RD risk. RESEARCH DESIGN AND METHODS: We identified all RD reports in FAERS between 2010-2019. We compared ADE signals between quinolones and selected medications that were previously associated with RD, and with reference medications not known to cause RD. For signal detection, we used two techniques: the proportional reporting ratio (PRR) and multi-item gamma Poisson shrinker (MGPS), which are known for their higher sensitivity and specificity for ADE signal detection, respectively. RESULTS: Moxifloxacin showed a positive and significant PRR signal for RD [PRR: 2.54 (1.60, 4.04)], and a marginally significant EBGM signal [EBGM: 2.21 (1.41, 3.02)]. CONCLUSION: Moxifloxacin is the only quinolone showing a positive disproportionality signal for RD. Further epidemiologic research is needed to clarify the association between moxifloxacin and RD risk.

Systemic quinolones and risk of acute liver failure I: Analysis of data from the US FDA adverse event reporting system.

BACKGROUND AND AIM: Quinolones are a potent and globally popular group of antibiotics that are used to treat a wide range of infections. Some case reports have raised concern about their possible association with acute hepatic failure (AHF). Data from the US FDA Adverse Event Reporting System were evaluated for signals of AHF in association with systemically administered quinolone antibiotics. METHODS: AHF reports between 1969 and 2019q2, with a focus on 2010-2019q2, were analyzed. Specifically, AHF reports linked to non-quinolone antibiotics of known hepatotoxicity were compared to reports with non-quinolone, non-hepatotoxic (reference) antibiotics; and AHF reports with quinolones were also compared to reports with the same group of reference antibiotics. Two disproportionality signal detection techniques (proportional reporting ratio, PRR, and empirical Bayes geometric mean, EBGM) were used to assess the AHF signal for both analyses. RESULTS: Only ciprofloxacin showed a marginal and significant AHF signal (PRR: 1.85 [1.21, 2.81]; EBGM: 1.54 [1.06, 1.81]); moxifloxacin, levofloxacin, and ofloxacin showed weak and nonsignificant signals. CONCLUSION: Further pharmacovigilance studies are required to confirm the association between ciprofloxacin and AHF seen in the present analysis.

Postmyocardial Infarction Statin Exposure and the Risk of Stroke with Weighting for Outcome Misclassification.

BACKGROUND: Observational healthcare data can be used for drug safety and effectiveness research. The use of inverse probability of treatment weights (IPW) reduces measured confounding under the assumption of accurate measurement of the outcome variable; however, many datasets suffer from systematic outcome misclassification. METHODS: We introduced a modification to IPW to correct for the presence of outcome misclassification. To demonstrate the utility of these modified weights in realistic settings, we investigated postmyocardial infarction statin use and the 1-year risk of stroke in the Clinical Practice Research Datalink. RESULTS: We computed an IPW-adjusted odds ratio (OR = 0.67; 95% confidence interval (CI) = 0.48, 0.93). We employed a technique to modify IPW for the presence of outcome misclassification using linked hospital records for outcome validation (modified IPW adjusted OR = 0.77; 95% CI = 0.52, 1.15) and compared the results with a meta-analysis of randomized controlled trials (RCTs) (pooled OR = 0.80; 95% CI = 0.74, 0.87). Finally, we present simulation studies to investigate the impact of model selection on bias reduction and variability. CONCLUSION: Ignoring outcome misclassification yielded biased estimates whereas the use of the modified IPW approach produced encouraging results when compared with the meta-analytic RCT findings.

Data on systematic review and meta-analysis of epidemiologic evidence on the association between perineal use of talc powder and risk of ovarian cancer.

This paper describes data from a systematic review and meta-analysis [1] conducted to identify and evaluate published peer reviewed evidence on the association between perineal use of talc powder and risk of ovarian cancer. These data were collected from multiple electronic bibliographic databases, as well as from grey literature sources, without applying time, language or other filters. A meta-analysis was conducted to quantitatively assess the ovarian cancer risk in relation to talc use and other potential risk factors.

Critical review of the association between perineal use of talc powder and risk of ovarian cancer.

Over the past four decades, there has been increasing concern that perineal use of talc powder, a commonly used personal care product, might be associated with an increased risk of ovarian cancer. OBJECTIVES: To critically review all available human epidemiological data on the relationship between perineal use of talc powder and ovarian cancer, with consideration of other relevant experimental evidence. METHODOLOGY: We identified 30 human studies for qualitative assessment of evidence, including 27 that were retained for further quantitative analysis. RESULTS: A positive association between perineal use of talc powder and ovarian cancer was found [OR: 1.28 (95% CI: 1.20-1.37)]. A significant risk was noted in Hispanics and Whites, in women applying talc to underwear, in pre-menopausal women and in post-menopausal women receiving hormonal therapy. A negative association was noted with tubal ligation. CONCLUSION: Perineal use of talc powder is a possible cause of human ovarian cancer.

Conditional validation sampling for consistent risk estimation with binary outcome data subject to misclassification.

PURPOSE: Misclassification of a binary outcome can introduce bias in estimation of the odds-ratio associated with an exposure of interest in pharmacoepidemiology research. It has been previously demonstrated that utilizing information from an internal randomly selected validation sample can help mitigate this bias. METHODS: Using a Monte Carlo simulation-based approach, we study the properties of misclassification bias-adjusted odds-ratio estimators in a contingency table setting. We consider two methods of internal validation sampling; namely, simple random sampling and sampling conditional on the original (possibly incorrect) outcome status. Additional simulation studies are conducted to investigate these sampling approaches in a multi-table setting. RESULTS: We demonstrate that conditional validation sampling, across a range of subsampling fractions, can produce better estimates than those based on an unconditional simple random sample. This approach allows for greater flexibility in the chosen categorical composition of the validation data, as well as the potential for obtaining a more efficient estimator of the odds-ratio. We further demonstrate that this relationship holds for the Mantel-Haenszel misclassification bias-adjusted odds-ratio in stratified samples. Recommendations for the choice of validation subsampling fraction are also provided. CONCLUSIONS: Careful consideration when choosing the sampling scheme used to draw internal validation samples can improve the properties of the outcome misclassification bias-adjusted odds-ratio estimator in a (multiple) contingency table.

A validation sampling approach for consistent estimation of adverse drug reaction risk with misclassified right-censored survival data.

Patient electronic health records, viewed as continuous-time right-censored survival data, can be used to estimate adverse drug reaction risk. Temporal outcome misclassification may occur as a result of errors in follow-up. These errors can be due to a failure to observe the incidence time of the adverse event of interest (due to misdiagnosis or nonreporting, etc) or an actual misdiagnosis of a competing adverse event. As the misclassifying event is often unobservable in the original data, we apply an internal validation sampling approach to produce consistent estimation in the presence of such errors. We introduce a univariate survival model and a cause-specific hazards model in which misclassification may also manifest as a diagnosis of an alternate adverse health outcome other than that of interest. We develop a method of maximum likelihood estimation of the model parameters and establish consistency and asymptotic normality of the estimators using standard results. We also conduct simulation studies to numerically investigate the finite sample properties of these estimators and the impact of ignoring the misclassification error.

Weighted estimation for confounded binary outcomes subject to misclassification.

In the presence of confounding, the consistency assumption required for identification of causal effects may be violated due to misclassification of the outcome variable. We introduce an inverse probability weighted approach to rebalance covariates across treatment groups while mitigating the influence of differential misclassification bias. First, using a simplified example taken from an administrative health care dataset, we introduce the approach for estimation of the marginal causal odds ratio in a simple setting with the use of internal validation information. We then extend this to the presence of additional covariates and use simulated data to investigate the finite sample properties of the proposed weighted estimators. Estimation of the weights is done using logistic regression with misclassified outcomes, and a bootstrap approach is used for variance estimation.