Misdiagnosis of amyotrophic lateral sclerosis in clinical practice in Europe and the USA: a patient chart review and physician survey.

OBJECTIVE: Delays in amyotrophic lateral sclerosis (ALS) diagnosis can result in compromised disease management and unnecessary costs. We examined the extent of ALS misdiagnosis in the US and Europe. METHODS: Data were collected via the Adelphi ALS Disease Specific Programme™, a cross-sectional survey of physicians and a medical chart review of their consulting patients with ALS in France, Germany, Italy, Spain, the UK (EU5), and the US. Between July 2020 and March 2021, eligible physicians (primary speciality neurology, active involvement in managing patients with ALS) abstracted data from patients (≥18 years old) with confirmed ALS. RESULTS: Overall, 138 physicians completed the survey (EU5 107, US 31), with data reviewed from 795 patient medical charts (EU5 568, US 227); 278 (35.0%) patients (EU5 183 [32.2%], US 95 [41.9%]) had received ≥1 initial misdiagnosis based on symptoms later attributed to ALS. Mean (SD) time from symptom onset to first healthcare professional consultation was 3.8 (5.2) months (EU5 4.3 [4.8] months, US 2.6 [5.8] months). Mean (SD) time from symptom onset to ALS diagnosis was 8.2 (12.5) months (EU5 9.6 [14.0] months, US 5.0 [6.8] months) and increased to 10.4 (17.9) for patients with a misdiagnosis (compared with 6.9 [7.2] for patients with no misdiagnosis). Physician-identified barriers to timely ALS diagnosis included the similarity of symptoms to other conditions and delayed referral to neurologists. CONCLUSIONS: Misdiagnosis of ALS is frequent, with a protracted diagnostic pathway. Targeted education of patients and physicians about signs and symptoms and benefits of prompt referral to multidisciplinary care are needed.

Use of clinical classifications software to address ICD coding transition in large healthcare databases analyzed via high-dimensional propensity scores.

PURPOSE: The EUPAS26595 study characterized the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other antiepileptic drugs using healthcare claims data and a high-dimensional propensity score (hd-PS) for confounding adjustment. The data contained several coding systems by design and an update in International Classification of Diseases (ICD) coding dictionary. Such coding heterogeneity can affect the performance of hd-PS, and manually coding harmonization is not feasible. Our objective was to explore the impact of code aggregation via Clinical Classifications Software (CCS) on the analysis of a large claims-based database using hd-PS. METHODS: Patients with epilepsy, who were new-users of an antiepileptic drug, were identified from the IBM® MarketScan® Research Databases. We used CCS categories to harmonize coding and compared the results with other alternatives. Incidence rate ratios (IRRs) were computed using modified Poisson regression model with a robust variance estimator. RESULTS: For January 2008-October 2015 (before ICD update), 34 833 eligible patients initiated levetiracetam and 52 649 initiated a comparator drug; IRR (95% CI) for ARF for the hd-PS analysis was 1.34 (0.72-2.50) without CCS categories and 1.30 (0.71-2.39) with CCS categories. For January 2008-December 2017 (including ICD coding change), 45 672 eligible patients initiated levetiracetam and 64 664 initiated a comparator drug; IRR (95% CI) for the hd-PS analysis was 1.34 (0.78-2.29) without CCS categories and 1.37 (0.80-2.34) with CCS categories. CONCLUSIONS: Using single-level CCS categories to overcome differences in coding provides consistent results and can be used in studies that use large claims data and hd-PS for adjustment.

Social media and internet search data to inform drug utilization: A systematic scoping review.

Introduction: Drug utilization is currently assessed through traditional data sources such as big electronic medical records (EMRs) databases, surveys, and medication sales. Social media and internet data have been reported to provide more accessible and more timely access to medications' utilization. Objective: This review aims at providing evidence comparing web data on drug utilization to other sources before the COVID-19 pandemic. Methods: We searched Medline, EMBASE, Web of Science, and Scopus until November 25th, 2019, using a predefined search strategy. Two independent reviewers conducted screening and data extraction. Results: Of 6,563 (64%) deduplicated publications retrieved, 14 (0.2%) were included. All studies showed positive associations between drug utilization information from web and comparison data using very different methods. A total of nine (64%) studies found positive linear correlations in drug utilization between web and comparison data. Five studies reported association using other methods: One study reported similar drug popularity rankings using both data sources. Two studies developed prediction models for future drug consumption, including both web and comparison data, and two studies conducted ecological analyses but did not quantitatively compare data sources. According to the STROBE, RECORD, and RECORD-PE checklists, overall reporting quality was mediocre. Many items were left blank as they were out of scope for the type of study investigated. Conclusion: Our results demonstrate the potential of web data for assessing drug utilization, although the field is still in a nascent period of investigation. Ultimately, social media and internet search data could be used to get a quick preliminary quantification of drug use in real time. Additional studies on the topic should use more standardized methodologies on different sets of drugs in order to confirm these findings. In addition, currently available checklists for study quality of reporting would need to be adapted to these new sources of scientific information.

Incidence of Acute Renal Failure in Patients Using Levetiracetam Versus Other Antiseizure Medications: A Voluntary Post-Authorization Safety Study.

INTRODUCTION: Acute kidney injury is an expected adverse drug reaction listed in the European Union (EU) Summary of Product Characteristics (SmPC) for levetiracetam, one of the most widely used modern antiseizure medications (ASMs). OBJECTIVE: We conducted a voluntary post-authorization safety study to characterize the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other ASMs. METHODS: New users of ASMs without prior renal dysfunction were identified and followed for 30 days in the IBM® MarketScan® database (USA, January 2008-December 2017). ARF was defined as a diagnosis on inpatient or emergency department claims. We estimated adjusted incidence rates, incidence rate ratios (IRRs), and incidence rate differences (IRDs) of ARF in patients initiating levetiracetam versus other ASMs. RESULTS: Overall, 110,336 patients were eligible for the monotherapy cohort and 96,215 were eligible for the polytherapy cohort. The overall crude rate of ARF following a new ASM was 6.0 and 6.5 per 10,000 patients for the 'monotherapy' and 'polytherapy' cohorts, respectively, in the first 30 days after the index date. In the monotherapy cohort, the IRR for ARF was 1.37 (95% confidence interval [CI] 0.80-2.34) and the corresponding IRD was 2.0 (95% CI - 1.12 to 5.12) additional ARFs per 10,000 patient-months. In the polytherapy cohort, the adjusted IRR for ARF was 0.94 (95% CI 0.51-1.74) and the corresponding IRD was - 0.42 cases per 10,000 patient-months (95% CI - 4.01 to 3.17). CONCLUSIONS: The rate of ARFs in ASM new users was very low. In patients without prior ASMs, the estimated difference in risk of ARF associated with initiation of levetiracetam versus initiation of other ASMs was small, with 95% CIs compatible with small protective or harmful effects. In patients receiving polytherapy, the difference was compatible with the null and the 95% CI with small protective or harmful effects.

SCOR: A secure international informatics infrastructure to investigate COVID-19.

Global pandemics call for large and diverse healthcare data to study various risk factors, treatment options, and disease progression patterns. Despite the enormous efforts of many large data consortium initiatives, scientific community still lacks a secure and privacy-preserving infrastructure to support auditable data sharing and facilitate automated and legally compliant federated analysis on an international scale. Existing health informatics systems do not incorporate the latest progress in modern security and federated machine learning algorithms, which are poised to offer solutions. An international group of passionate researchers came together with a joint mission to solve the problem with our finest models and tools. The SCOR Consortium has developed a ready-to-deploy secure infrastructure using world-class privacy and security technologies to reconcile the privacy/utility conflicts. We hope our effort will make a change and accelerate research in future pandemics with broad and diverse samples on an international scale.

Adverse Drug Reaction Risk Measures: A Comparison of Estimates from Drug Surveillance and Randomised Trials.

BACKGROUND: Most drug regulatory agencies and pharmaceutical companies hold databases of spontaneous reports of suspected adverse drug reactions (ADRs). Detection systems for ADR signals have been created by specialists to analyse such reports, based on the concept of disproportionality, in order to support safety decision making. However, these measures are often misinterpreted by non-specialists in pharmacovigilance. OBJECTIVES: Our aim was to assess agreement between estimates of risk from spontaneous reports of suspected ADRs and estimates of risks of ADRs from randomised controlled trials (RCTs). METHODS: From 150 drugs randomly selected from the US Food and Drug Administration's Adverse Event Reporting System (FAERS), we identified drugs where FAERS provided reporting odds ratios (RORs) and corresponding systematic reviews from the Cochrane database gave (pooled) odds ratios (ORs) for the same drugs and adverse reactions. We assessed agreement between (ln) RORs and (ln) ORs using the Pearson correlation coefficient and the Bland-Altman agreement method, and performed sensitivity analyses. RESULTS: We identified 6 drugs and 125 ADRs. Overall, there was a weak correlation (r = 0.20) between RORs (FAERS) and ORs (RCTs). However, we observed a stronger correlation (r = 0.78) between RORs and ORs for one drug (roflumilast) that received market approval relatively recently (2011). CONCLUSIONS: Spontaneous reporting of suspected ADRs is an important tool for regulatory agencies and pharmaceutical companies in making decisions and detecting drug safety signals. Although there was moderate-to-strong agreement between ADR risk estimates from drug surveillance and RCTs for one drug, this study illustrates the current recommendations not to use disproportionality measures as valid proxies for risk estimates.

Getting to Long-Term Effectiveness and Safety of Attention-deficit Hyperactivity Disorder Medications.

Attention-deficit hyperactivity disorder (ADHD) medication use has dramatically increased in youth worldwide. Recent prevalence data in some European countries show expanded use with one country now matching US usage. Still, substantial geographic differences by country remain regarding the extent to which children receive ADHD medications. These geographic differences by country raise research questions about which country's prevalence data represents appropriate medication use. We urgently need country level studies to contribute to our understanding of an appropriate prevalence of ADHD medication use.

Latest trends in ADHD drug prescribing patterns in children in the UK: prevalence, incidence and persistence.

OBJECTIVES: To investigate attention deficit and hyperactivity disorder (ADHD) drug prescribing in children under 16 years old in the UK between 1992 and 2013. METHODS: All patients under 16 registered in the Clinical Practice Research Datalink (CPRD) with a minimum of 1 year of observation time and who received at least one prescription of any ADHD drug between 1 January 1992 and 31 December 2013.Trends in prevalence and incidence of use of ADHD drugs in children were calculated between 1995 and 2013 and persistence in new users was estimated. RESULTS: The prevalence of ADHD drug use in children under 16 increased 34-fold overall, rising from 1.5 95% CI (1.1 to 2.0) per 10 000 children in 1995 to 50.7 95% CI (49.2 to 52.1) per 10 000 children in 2008 then stabilising to 51.1 95% CI (49.7 to 52.6) per 10 000 children in 2013. The rate of new users increased eightfold reaching 10.2 95% CI (9.5 to 10.9) per 10 000 children in 2007 then decreasing to 9.1 95% CI (8.5 to 9.7) per 10 000 children in 2013. Although prevalence and incidence increased rather steeply after 1995, this trend seems to halt from 2008 onwards. We identified that 77%, 95% CI (76% to 78%) of children were still under treatment after 1 year and 60% 95% CI (59% to 61%) after 2 years. CONCLUSIONS: There was a marked increase in ADHD drug use among children in the UK from 1992 until around 2008, with stable levels of use since then. UK children show relatively long persistence of treatment with ADHD medications compared to other countries.

Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK.

INTRODUCTION: Over 70% of cervical cancers are related to human papillomavirus types 16 and 18. In 2008, the vaccine Cervarix, protecting against these two strains, was introduced into the routine UK immunisation programme for girls aged 12-13 years, with a catch-up in girls aged up to 18 years. As part of the risk management planning for this new campaign, the Medicines and Healthcare products Regulatory Agency (MHRA) anticipated a range of conditions, including chronic fatigue syndrome, which might be reported as adverse events in temporal association with the vaccine. METHODS: Near-real time 'observed vs. expected' analyses were conducted comparing the number of reports of fatigue syndromes submitted via the MHRA's Yellow Card passive surveillance scheme to the expected number, using background rates calculated from the Clinical Practice Research Datalink (CPRD) and estimates of vaccination coverage. Subsequently, an ecological analysis and a self-controlled case series (SCCS), both using CPRD, compared the incidence rate of fatigue syndromes in girls before and after the start of the vaccination campaign and the risk in the year post-vaccination compared to other periods. RESULTS: The number of spontaneous reports of chronic fatigue following Cervarix vaccination was consistent with estimated background rates even assuming low reporting. Ecological analyses suggested that there had been no change in the incidence of fatigue syndromes in girls aged 12-20 years after the introduction of the vaccination despite high uptake (IRR: 0.94, 95% CI: 0.78-1.14). The SCCS, including 187 girls, also showed no evidence of an increased risk of fatigue syndromes in the year post first vaccination (IRR: 1.07, 95% CI: 0.57-2.00, p=0.84). DISCUSSION: The successful implementation of an enhanced pharmacovigilance plan provided immediate reassuring evidence that there was no association between vaccination with Cervarix and an increased risk of chronic fatigue syndromes. This has now also been further demonstrated in more comprehensive epidemiological studies.