Measure Of Disproportionality Research Articles

Antibacterial-associated acute kidney injury among older adults: A post-marketing surveillance study using the FDA adverse events reporting system.

Antibacterials induce a differential risk of acute kidney injury (AKI) in older adults. This study investigated the reporting risk of AKI associated with antibacterials using the individual case safety reports (ICSRs) submitted to the Food and Drug Administration Adverse Event Reporting System (FAERS) database. A case/non-case method was used to assess AKI risk associated with antibacterials between 1 January 2000 and 30 September 2021. Cases were ICSRs for antibacterials with AKI as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'Renal and urinary disorders' disorders. The analyses were completed on a de-duplicated data set containing only the recent version of the ICSR. Signals were defined by a lower 95% confidence interval (CI) of reporting odds ratio (ROR) ≥ 2, proportional reporting ratio (PRR) ≥ 2, information component (IC) > 0, Empirical Bayes Geometric Mean (EBGM) > 1 and reports ≥4. Sensitivity analyses were conducted a priori to assess the robustness of signals. A total of 3 680 621 reports on ADEs were retrieved from FAERS over the study period, of which 92 194 were antibacterial reports. Gentamicin, sulfamethoxazole, trimethoprim and vancomycin consistently gave strong signals of disproportionality on all four disproportionality measures and across the different sensitivity analyses: gentamicin (ROR=2.95[2.51-3.46]), sulfamethoxazole (ROR=2.97[2.68-3.29]), trimethoprim (ROR=2.81[2.29-3.46]) and vancomycin (ROR=3.35[3.08-3.64]). Signals for gentamicin, sulfamethoxazole, trimethoprim and vancomycin were confirmed by using antibacterials as a comparator, adjusting for drug-related competition bias and event-related competition bias.

Amyotrophic Lateral Sclerosis as an Adverse Drug Reaction: A Disproportionality Analysis of the Food and Drug Administration Adverse Event Reporting System

Amyotrophic lateral sclerosis is a fatal progressive disease with a still unclear multi-factorial etiology. This study focused on the potential relationship between drug exposure and the development of amyotrophic lateral sclerosis by performing a detailed analysis of events reported in the FDA Adverse Event Reporting System database. The FDA Adverse Event Reporting System quarterly data (January 2004-June 2020) were downloaded and deduplicated. The reporting odds ratios and their 95% confidence intervals were calculated as a disproportionality measure. The robustness of the disproportion was assessed accounting for major confounders (i.e., using a broader query, restricting to suspect drugs, and excluding reports with amyotrophic lateral sclerosis as an indication). Disproportionality signals were prioritized based on their consistency across analyses (reporting odds ratio stability). We retained 1188 amyotrophic lateral sclerosis cases. Sixty-two drugs showed significant disproportionality for amyotrophic lateral sclerosis onset in at least one analysis, and 31 had consistent reporting odds ratio stability, including tumor necrosis factor-alpha inhibitors and statins. Disproportionality signals from ustekinumab, an immunomodulator against interleukins 12-23 used in autoimmune diseases, and the anti-IgE omalizumab were consistent among analyses and unexpected. For each drug emerging as possibly associated with amyotrophic lateral sclerosis onset, biological plausibility, underlying disease, and reverse causality could be argued. Our findings strengthened the plausibility of a precipitating role of drugs primarily through immunomodulation (e.g., tumor necrosis factor-alpha, ustekinumab, and omalizumab), but also by impacting metabolism and the musculoskeletal integrity (e.g., statins and bisphosphonates). Complement and NF-kB dysregulation could represent interesting topics for planning translational mechanistic studies on amyotrophic lateral sclerosis as an adverse drug effect.

Immune Checkpoint Inhibitors and Venous Thromboembolism: An Analysis of the WHO Pharmacovigilance Database.

Data on venous thromboembolic events (VTEs) in patients receiving immune checkpoint inhibitors (ICIs) are scarce and conflicting. This study investigated the risk of reporting VTEs associated with ICIs in comparison with all other anticancer drugs. The World Health Organization pharmacovigilance database (VigiBase), comprising >30 million individual case safety reports, was queried. All reports on patients with cancer, involving at least one anticancer drug as a suspect or interacting drug and registered from January 1, 2008, to May 31, 2021, were included. The association between ICIs and the risk of reporting VTEs was estimated using the reporting odds ratio (ROR) as a measure of disproportionality with all other anticancer drugs as comparators. RORs were estimated as crude and adjusted RORs for age, sex, and other medications (excluding anticancer drugs) associated with risk of VTEs. Among 1,196 patients experiencing VTEs after ICI treatment, the median age was 65years and 57.6% were men. Anti-PD-1 agents (62.5%) were the most frequently reported. ICIs were not associated with higher reporting of VTEs when compared with other anticancer drugs (crude ROR 0.63, 95% confidence interval (CI) 0.60 to 0.67 and adjusted ROR 0.70, 95% CI 0.65-0.74). No signal of disproportionate reporting was found when considering each class of ICIs. In conclusion, ICIs were not associated with higher reporting of VTEs, in comparison with all other anticancer drugs in a large-scale pharmacovigilance database. Owing to the limitations inherent to pharmacovigilance studies, prospective studies, including an adequate comparison group, are needed to assess the risk of VTEs in ICI-treated patients.

Should methods of correction for multiple comparisons be applied in pharmacovigilance?


 Purpose. In pharmacovigilance, spontaneous reporting databases are devoted to the early detection of adverse event ‘signals’ of marketed drugs. A common limitation of these systems is the wide number of concurrently investigated associations, implying a high probability of generating positive signals simply by chance. However it is not clear if the application of methods aimed to adjust for the multiple testing problems are needed when at least some of the drug-outcome relationship under study are known. To this aim we applied a robust estimation method for the FDR (rFDR) particularly suitable in the pharmacovigilance context.
 Methods. We exploited the data available for the SAFEGUARD project to apply the rFDR estimation methods to detect potential false positive signals of adverse reactions attributable to the use of non-insulin blood glucose lowering drugs. Specifically, the number of signals generated from the conventional disproportionality measures and after the application of the rFDR adjustment method was compared.
 Results. Among the 311 evaluable pairs (i.e., drug-event pairs with at least one adverse event report), 106 (34%) signals were considered as significant from the conventional analysis. Among them 1 resulted in false positive signals according to rFDR method.
 Conclusions. The results of this study seem to suggest that when a restricted number of drug-outcome pairs is considered and warnings about some of them are known, multiple comparisons methods for recognizing false positive signals are not so useful as suggested by theoretical considerations.

Post-marketing safety surveillance of erenumab: new insight from Eudravigilance

ABSTRACT Background We aimed at evaluating adverse drug reactions during the post-marketing phase with erenumab as the suspected/interacting drug in Eudravigilance, with the final goal of investigating the consistency of the disproportionality signals (DS) for erenumab in Eudravigilance and the American Food and Drug Administration Adverse Event Reporting System (FDA FAERS) and undetected DS from Eudravigilance. Research design and methods Eudravigilance was screened in the period from October 2019 to October 2020. Disproportionality measure was performed using the Reporting Odds Ratio (ROR) according to the guidelines by the European Medicine Agency and using sumatriptan as the control group. Results 3381 cases were reported in the study period. Forty DS were identified both in Eudravigilance and FAERS. Sixteen DS were not identified in FAERS, 10 DS were found to have biological probability and six DS were considered false-positive and potentially related to confounding by indication. The three system organ classes with the highest proportion of adverse events were general disorders and administration site conditions (16.12%), nervous system disorders (15.95%), and gastrointestinal disorders (13.59%). Conclusions Adverse events reports were mostly reported as non-serious. Co-analysis of multiple spontaneous reported databases unveiled undetected DS for erenumab in individual databases. Future studies should be conducted to confirm the associations and potential clinical implications.

Association between myocarditis and antipsychotics other than clozapine: a systematic literature review and a pharmacovigilance study using VigiBase

ABSTRACT Introduction Pharmacovigilance studies have definitely established that clozapine can cause myocarditis. Two published reviews suggested that on rare occasions other antipsychotics may induce myocarditis. Areas covered This review explored myocarditis associated with antipsychotics other than clozapine by conducting a systematic search of the literature and critically analyzing the current data in VigiBase compared to the data on clozapine-associated myocarditis. VigiBase is the World Health Organization’s global pharmacovigilance database that uses a statistical signal for associations with a logarithmic measure of disproportionality called the information component (IC). Expert opinion For quetiapine, VigiBase provided 106 reports of myocarditis and a significant statistical signal (IC = 1.8; IC025 = 1.5) which was confounded by 48% (51/106) with clozapine co-prescription. Combining the literature and VigiBase cases provided five probable myocarditis cases during quetiapine monotherapy (4 after overdose or rapid titration). For olanzapine, VigiBase provided 107 reports of myocarditis and a significant statistical signal (IC = 2.1; IC025 = 1.8) probably explained by 77% (82/107) using clozapine co-prescription. Combining the literature and VigiBase cases provided one probable myocarditis case during olanzapine monotherapy. Combining the literature and VigiBase provided another three probable cases during therapy with other antipsychotics during overdose or titration with a high dose.

ASEAN Policy Responses to COVID-19 Pandemic: Adaptation and Experimentation Policy: A Study of ASEAN Countries Policy Volatility for COVID-19 Pandemic

In response to the COVID-19 pandemic, this paper provides valuable information to establish new comparative policies between ASEAN countries. The study used disproportionate policy-making that stimulated the understanding of different adaptive strategies. The paper identified the extent of government response policy as a range of proportionate public involvement. The measure of disproportionality was obtained by calculating the regional differentiation in a particular country’s average response to a crisis. This study found that six ASEAN countries are disproportional in their Policy Response to the COVID-19 Pandemic. Thailand is ranked the highest and classified as the most prepared country in terms of Global Health Security, and four countries are classified as normo-action. Indeed, Thailand is one of the countries with the most-prepared health security. Nonetheless, countries deemed less prepared and underreacting include Laos, Cambodia, Malaysia, Singapore, Indonesia, Myanmar, and the Philippines, which have all witnessed continuous rapid growth in COVID-19 infections.

Decision Tree-Based Data Stratification Method for the Minimization of the Masking Effect in Adverse Drug Reaction Signal Detection

Data masking is an inborn defect of measures of disproportionality in adverse drug reactions signal detection. Some improved methods which used gender and age for data stratification only considered the patient-related confounding factors, ignoring the drug-related influencing factors. Due to a large number of reports and the high proportion of antibiotics in the Chinese spontaneous reporting database, this paper proposes a decision tree-stratification method for the minimization of the masking effect by integrating the relevant factors of patients and drugs. The adverse drug reaction monitoring reports of Jiangsu Province in China from 2011 to 2018 were selected for this study. First, the age division interval was determined based on the statistical analysis of antibiotic-related data. Secondly, correlation analysis was conducted based on the patient’s gender and age respectively with the drug category attributes. Thirdly, the decision tree based on age and gender was constructed by the J48 algorithm, which was used to determine if drugs belonged to antibiotics as a classification label. Fourthly, some performance evaluation indicators were constructed based on the data of drug package inserts as a standard signal library: recall, precision, and F (the arithmetic harmonic mean of recall and precision). Finally, four experiments were carried out by means of the proportional reporting ratio method: non-stratification (total data), gender-stratification, age-stratification and decision tree-stratification, and the performance of the signal detection results was compared. The experimental results showed that the decision tree-stratification was superior to the other three methods. Therefore, the data-masking effect can be further minimized by comprehensively considering the patient and drug-related confounding factors.

Reporting of Acute Inflammatory Neuropathies with COVID-19 Vaccines: Subgroup Disproportionality Analyses in VigiBase.

Since marketing authorization, cases of neuralgic amyotrophy (NA), facial paralysis/Bell’s palsy (FP/BP), and Guillain-Barré syndrome (GBS) were reported with COVID-19 vaccines of different technologies. This study aimed to assess whether NA, FP/BP, and GBS were more frequently reported in VigiBase with COVID-19 vaccines (of any technologies) than with other viral vaccines, over the full database and across potential risk groups by sex and age. The reporting odds ratio (ROR) with 95% confidence interval (95% CI) was used as the measure of disproportionality and subgroup disproportionality analyses were performed by sex and age. Out of 808,906 safety reports with COVID-19 vaccines, 57 (0.01%) reported NA, 3320 (0.4%) FP/BP, and 632 (0.1%) GBS. There were not signals of disproportionate reporting for NA and GBS with COVID-19 vaccines against other viral vaccines. FP/BP was disproportionately more frequently reported with COVID-19 vaccines than with other viral vaccines over the full database (ROR 1.12, 95%CI 1.07–1.17), in males (ROR 1.65, 95%CI 1.54–1.78) and in age subgroups 65–74 years (ROR 1.21, 95%CI 1.05–1.39) and ≥75 years (ROR 1.84, 95%CI 1.52–2.22). Albeit not proving causation, these findings might support clinicians in decision-making for patients potentially at risk for developing an acute inflammatory neuropathy with COVID-19 vaccines.

Drug-induced Urinary Retention: An Analysis of a National Spontaneous Adverse Drug Reaction Reporting Database

BackgroundNumerous drugs have been associated with urinary retention (UR), but updated information on drugs that may induce UR is limited. ObjectiveTo evaluate drug-induced UR using the Italian spontaneous adverse drug reactions (ADRs) reporting database. Design, setting, and participantsWe selected all suspected spontaneous reports of drug-induced UR collected into the Italian spontaneous reporting system (SRS) database from its inception to June 30, 2019. Outcome measurements and statistical analysisThe Mantel-Haenszel χ2 test and the Mann-Whitney U test were performed for statistical comparisons of categorical and continuous variables, respectively. As a measure of disproportionality, we calculated the reporting odds ratios (RORs) with corresponding 95% confidence intervals using a statistical case/noncase methodology. Results and limitationsA total of 506 383 ADR reports were received in the Italian SRS database during the study period. Of these, 421 reports (0.1%) included UR-related ADRs, for a total of 497 suspected drugs. The median (interquartile range [IQR]) age of patients experiencing UR was 67 (47–77) yr. Overall, 174 (41.3%) ADR reports were considered serious. One-third of male patients experiencing UR suffered from benign prostatic hyperplasia, followed by diabetes mellitus (N = 58, 13.8%), and bladder-related disorders (N = 21, 5.0%). The median lag time between the start of drug treatment and UR onset was 7 (IQR 1–47.5) d. Overall, a statistically significant ROR was reported for 39 individual drugs, and for five (12.8%) of them (dapagliflozin, gabapentin, lithium, celecoxib, and piroxicam) UR was not described in their summary of product characteristics. Limitations include under-reporting and selective over-reporting of suspected ADRs and lacking information on the number of drug users. ConclusionsA disproportionality analysis identified five potentially new UR signals for dapagliflozin, gabapentin, lithium, celecoxib, and piroxicam, requiring further evaluation. Patient summaryIn this analysis of the Italian spontaneous reporting system database, we found new urinary retention signals, requiring further evaluation, for dapagliflozin, gabapentin, lithium, celecoxib, and piroxicam.

The impact of anti-TNFα agents on weight-related changes: new insights from a real-world pharmacovigilance study using the FDA adverse event reporting system (FAERS) database

ABSTRACT Introduction Studies in patients with immune-mediated inflammatory diseases (IMIDs) have inconsistently suggested that anti-TNFα therapy may be associated with excessive weight gain. Areas covered We performed a nested case/non-case analysis to investigate the anti-TNF-α inhibitor-associated body-changes in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. The risk was expressed as a measure of disproportionality using the reporting odds ratio (ROR) while adjusting for sex, drugs known to cause weight gain and reporter type. We also performed a time-to-onset (TTO) analysis of body weight-related events. Results Infliximab was the most commonly involved TNF-α inhibitor in body weight-related changes, reaching an aROR of 1.42 (95%CI:1. 26; 1.59). An increased risk was especially found in patients affected by rheumatic disorders, both in the adult and pediatric population. The median TTO after the start of anti- TNFα therapy was about 6–7 months for both children and adults. Conclusions Given the potential effect of these agents on the excess weight gain in IMIDs patients, continuous attention for this side effect with appropriate counseling regarding lifestyle modifications are warranted, especially in those at high risk for obesity.

Association between anaphylaxis and anti-influenza drug use: An analysis of the Japanese Adverse Drug Event Report database.

We aimed to investigate the association between anaphylaxis and anti-influenza drug use using the Japanese Adverse Drug Event Report (JADER) database, a national spontaneous reporting database in Japan. We surveyed registered cases from the JADER database between April 2004 and November 2019. The target drugs were five anti-influenza drugs, namely oseltamivir, zanamivir, peramivir, laninamivir, and baloxavir. Adverse events associated with anaphylaxis, "anaphylactic reaction," "anaphylactic shock," "anaphylactoid reaction," and "anaphylactoid shock," were evaluated. The association between anaphylaxis and anti-influenza drug use was assessed by calculating the reporting odds ratio (ROR) and information component (IC) as a measure of disproportionality. Signals were considered positive if the lower limit of the 95% confidence interval (CI) of ROR was > 1, and that of IC was > 0. The number of anaphylaxis cases associated with anti-influenza drug use was 199 (0.9%). Signals were detected for inhaled laninamivir (ROR: 4.24 [95% CI: 3.06-5.88], IC: 1.83 [1.35-2.30]), intravenous peramivir (ROR: 2.97 [2.11-4.17], IC: 1.40 [0.90-1.89]), and oral baloxavir (ROR: 3.05 [2.22-4.18], IC: 1.44 [0.98-1.90]). Conversely, signals were not detected for oral oseltamivir or inhaled zanamivir. Although zanamivir and laninamivir were used as dry powder inhalers containing lactose as an additive, they differed in terms of signal detection. Our analysis indicated that the signal of anaphylaxis may varies based on the main component or dosage form of each anti-influenza drug. Appropriate use of these drugs is essential to prevent anaphylaxis and improve health status.

Torsade de pointes associated with chloroquine, hydroxychloroquine, and azithromycin: a retrospective analysis of individual case safety reports from VigiBase.

PurposeTo analyze the cases of torsade de pointes (TdP) and related symptoms reported in association with chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZT) to the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase) using qualitative and quantitative pharmacovigilance approaches.MethodsThe main characteristics of the ICSRs reporting TdP with CQ, HCQ, and AZT have been summarized. Co-reported drugs with risk to cause QT prolongation have been described. Reporting odds ratios (RORs) as a measure of disproportionality for reported TdP and individual drugs have been calculated.ResultsOne hundred seventy ICSRs reporting TdP in association with the drugs of interest were identified (CQ: 11, HCQ: 31, CQ + HCQ: 1, HCQ + AZT: 27, AZT: 100). From these, 41 (24.3%) were received during the pandemic period (December 2019 to February 2021). The median age of the patients was 63, 53, and 63 years old for CQ, HCQ, and AZT, respectively. Reports included concomitant use of other QT-prolonging drugs (CQ 25.0%, HCQ 71.2%, AZT 64.6%). A proportion of the cases were fatal (CQ 25.0%, HCQ 8.6%, AZT 16.1%). Increased disproportionality has been found for the individual drugs and TdP: CQ (ROR: 7.41, 95% confidence interval (CI): 3.82, 12.96), HCQ (ROR: 8.49, 95% CI: 6.57, 10.98), azithromycin (ROR: 8.06, 95% CI: 6.76, 9.61). Disproportionality was also found for other related symptoms, Standardized MedDRA Query for torsade de pointes/QT prolongation (narrow): CQ (ROR: 11.95, 95% CI: 10.04–14.22); HCQ (ROR: 20.43, 95% CI: 19.13, 21.83), AZT (ROR: 7.78, 95% CI: 7.26, 8.34).ConclusionsThe prescription of CQ, HCQ, and AZT should be restricted to therapeutic indications with established positive benefit/risk profile. Doctors and patients should be aware of this potential adverse reaction especially when several risk factors are present.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00228-021-03133-w.

Cardiovascular Safety Profile of Romosozumab: A Pharmacovigilance Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS)

Background: Cardiovascular safety concerns for major cardiovascular events (MACE) were raised during the clinical trials of romosozumab. We aimed to evaluate the cardiovascular safety profile of romosozumab in a large pharmacovigilance database. Methods: All cases reported between January 2019 and December 2020 where romosozumab was reported were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). The outcome of interest was MACE (myocardial infarction (MI), stroke, or cardiovascular death). A disproportionality analysis was conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals. Disproportionality analyses were stratified by sex and reporting region (US, Japan, other). Results: Of the 1995 eligible cases with romosozumab, the majority (N = 1188; 59.5%) originated from Japan. Overall, 206 suspected MACE reports were identified, of which the majority (n = 164; 13.8%) were from Japan, and 41 (5.2%) were from the United States (US). Among Japanese reports, patients were older and more frequently male than reports from the US. Similarly, cases with a reported MACE were older and had higher reports of cardioprotective drugs than those without cardiovascular events. Elevated reports for MACE (ROR 4.07, 95% CI: 2.39–6.93) was identified overall, which was primarily driven by the significant disproportionality measures in the Japanese reports. Conclusions: The current pharmacovigilance study identified a potential signal for elevated MACE, particularly in Japan. The results support the current safety warnings from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to avoid use in high-risk patients.

Relative Risk Analysis of Liver-related Adverse Drug Reactions in Children Based on China’s National Spontaneous Reporting System

To compare the risk of liver-related adverse drug reactions (ADRs) in children and adults. A case/non-case analysis on spontaneous reports based on the China National Adverse Drug Reactions Monitoring System database were conducted, focusing on events of liver-related ADRs in children younger than 14years of age. Both the relative risk of liver-related ADRs in children vs entire population and the risk stratification in children were expressed as a measure of disproportionality using the reporting odds ratio (ROR). There were 1206 cases of pediatric liver-related ADRs identified from 2012 to 2016, accounting for 2.82% of the entire population. The greatest ROR values in children from 0 to 14years vs the entire population were observed for analgesics (3.97, 95% CI 3.27-4.81), respiratory (2.60, 95% CI 1.04-6.43), antineoplastic (2.29, 95% CI 2.02-2.58), immunomodulatory (1.91, 95% CI 1.44-2.53), and antimicrobial agents (1.47, 95% CI 1.33-1.63). Notably, infants aged 0-1years showed significantly greater risk (3.14, 95% CI 2.85-3.48) of liver-related ADRs than the other age groups of children. For infants, analgesics (3.21, 95% CI 2.20-4.66) and antimicrobials (3.15, 95% CI 2.50-3.97) agents were found to have the greatest adjusted RORs than other drug categories. The highest RORs were found for meropenem, amoxicillin, fluconazole, vancomycin, cefaclor, and ceftazidime in the antimicrobial agents for infants. Children are sensitive to liver-related ADRs caused by several specific drug categories, and infants are the most sensitive.

A Pharmacovigilance Study of Adverse Drug Reactions Reported for Cardiovascular Disease Medications Approved Between 2012 and 2017 in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

Between 2012 and 2017, the FDA approved 29 therapies for a cardiovascular disease (CVD) indication. Due to the limited literature on patient safety outcomes for recently approved CVD medications, this study investigated adverse drug reports (ADRs) reported in the FDA Adverse Event Reporting System (FAERS). A disproportionality analysis of spontaneously reported ADR was conducted. Reports in FAERS from Quarter 1, 2012, through Quarter 1, 2019, were compiled, allowing a 2-year buffer following drug approval in 2017. Top 10 reported ADRs and reporting odds ratios (ROR; confidence interval (CI)), a measure of disproportionality, were analyzed and compared to drugs available prior to 2012 as appropriate. Of 7,952,147 ADR reports, 95,016 (1.19%) consisted of reports for newly approved CVD medications. For oral anticoagulants, apixaban had significantly lower reports for anemia and renal failure compared to dabigatran and rivaroxaban but greater reports for neurological signs/symptoms, and arrhythmias. Evaluating heart failure drugs, sacubitril/valsartan had greater reports for acute kidney injury, coughing, potassium imbalances, and renal impairment but notably, lower for angioedema compared to lisinopril. Assessing familial hypercholesterolemia drugs, alirocumab had greater reports for joint-related-signs/symptoms compared to other agents in this category. A newer pulmonary arterial hypertension treatment, selexipag, had greater reports of reporting for bone/joint-related-signs/symptoms but riociguat had greater reports for hemorrhages and vascular hypotension. Pharmacovigilance studies allow an essential opportunity to evaluate the safety profile of CVD medications in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved CVD medications.

Safety of antipsychotic drugs: A systematic review of disproportionality analysis studies

Antipsychotic drugs are commonly prescribed, mainly for the treatment of schizophrenia and other psychotic disorders. Disproportionality analysis of pharmacovigilance data from national and international databases have been recently utilized to investigate the side-effect profiles of antipsychotics and have provided unique insights of their safety. Among several national and international spontaneous reporting databases the databases of the World Health Organization (VigiBase), of the European Medicines Agency (EudraVigilance) and the US Food and Drug Administration (FAERS) incorporate millions of Individual Case Safety Reports. The aim of our study was to systematically review published disproportionality analyses on antipsychotic drugs, in order to summarize the current state of methodology and potential strengths of this analysis while highlighting safety signal generated for these pharmacological group. PubMed was searched using a search algorithm combining terms for antipsychotic drugs and disproportionality analysis. A total of 39 articles were found to be eligible corresponding to 38 original disproportionality studies. Different measures of disproportionality were used in each study: reporting odds ratio (ROR), proportional reporting ratio (PRR), empirical Bayes geometric mean (EBGM) and the information component (IC). Despite the inherent limitations of the pharmacovigilance databases disproportionality analysis provides complemented evidence from RCTs on the safety of antipsychotics, especially regarding participants often excluded from RCTs, such as pregnant and breastfeeding women, children and participants with drug abuse, comorbidities or concomitant medications.

Measures of vote-seat disproportionality for incomplete data

Measures of the proportionality of distributions are used across disciplines. ‘Disproportionality indices’ represent an application in politics, comparing the seat allocation in parliaments to the votes expressed for political parties. Disproportionality in elections is particularly high when many votes are expressed for parties not entering parliament; in some elections such ‘wasted votes’ add up to two-digit vote percentages. However, ‘wasted votes’ for small parties below the electoral threshold, as well as votes for non-partisan candidates, are often not listed in detail in election statistics, and are instead lumped together in residual categories such as ‘Others’ or ‘Independents’. This can hide major discrepancies between vote and seat distributions. This risks introducing systematic bias into the analysis of elections. This paper discusses several theoretically based methods to estimate indices of disproportionality for incomplete data, based on different theoretical scenarios concerning the distribution of votes and seats, and inspired by Taagepera’s method of ‘logical boundaries’. Empirical tests, relying on a dataset of 735 parliamentary elections worldwide, show that residual categories substantially affect indices of disproportionality. Several methods can considerably improve the measurement validity compared to the frequently used ‘naive’ procedures.

Legal, Political Science, and Economics Approaches to Measuring Malapportionment: The U.S. House, Senate, and Electoral College 1790–2010

ObjectiveWe compare and contrast methods for measuring malapportionment from different disciplines: law, political science, and economics.MethodsWith data from the U.S. House, Senate, and Electoral College (EC) over the period 1790–2010, we compare disproportionality measures and compare both across time and between institutions.ResultsWe demonstrate that which approach to measurement we take can dramatically affect some of the conclusions we reach. However, we also demonstrate that the House and the EC are hardly malapportioned, regardless of which measure we use, while the level of malapportionment we observe in the Senate can depend on which measure we use.ConclusionSince there are many axiomatic properties we might wish to satisfy, no one measure is uniformly best with respect to all feasible desiderata. However, one measure, the minimum population needed to win a majority, offers a readily comparable measure across legislatures and jurisdictions, and is easy for nonspecialists to understand.

Glucagon-like peptide-1 analogues and thyroid cancer: An analysis of cases reported in the European pharmacovigilance database.

The use of glucagon-like peptide-1 (GLP-1) analogues has been linked to the risk of thyroid cancer. Spontaneous reports can provide information about rare adverse events occurring after the time of marketing. Our objective was to detect, from the European pharmacovigilance database (EudraVigilance), a signal of thyroid cancer during GLP-1 analogues treatment in patients with diabetes. Herein, we analysed all reports of thyroid cancer reported with GLP-1 analogues in EudraVigilance database from their first marketing authorization till 30 January 2020. A case/non-case method was used to assess the association between thyroid cancer and GLP-1 analogues, calculating proportional reporting ratios (PRRs) and their 95% confidence interval (CI) as a measure of disproportionality. The cases were identified with Medical Dictionary for Regulatory Activities (MedDRA) version 22.1. There were 11243 cases of thyroid cancer and related preferred terms (PTs) in the 6665794 reports recorded in EudraVigilance during the study period. GLP-1 analogues were involved in 236 cases. Exenatide, liraglutide and dulaglutide met the criteria to generate a safety signal, suggesting that thyroid cancer is reported relatively more frequently in association with these drugs than with other medicinal products. The association was strongest for liraglutide followed by exenatide with PRR of 27.5 (95% CI, 22.7-33.3) and 22.5 (95% CI, 17.9-28.3), respectively. Disproportionality was also observed for GLP-1 analogues and individual identified preferred term, that is thyroid cancer (N=111), medullary thyroid cancer (N=64) and thyroid neoplasm (N=46) with PRR of 14.4 (95% CI, 11.8-17.4), 221.5 (95% CI, 155.7-315.1) and 35.5 (95% CI, 25.9-48.5), respectively. Our findings showed disproportionality for thyroid cancer, medullary thyroid cancer and thyroid neoplasm in patients treated with GLP-1 analogues. We have found evidence from spontaneous reports that GLP-1 analogues are associated with thyroid cancer in patients with diabetes.