Testing bias in clinical databases: methodological considerations

<p>Abstract</p> <p>Background</p> <p>Laboratory testing in clinical practice is never a random process. In this study we evaluated testing bias for neutrophil counts in clinical practice by using results from requested and non-requested hematological blood tests.</p> <p>Methods</p> <p>This study was conducted using data from the Utrecht Patient Oriented Database. This clinical database is unique, as it contains physician requested data, but also data that are not requested by the physician, but measured as result of requesting other hematological parameters. We identified adult patients, hospitalized in 2005 with at least two blood tests during admission, where requests for general blood profiles and specifically for neutrophil counts were contrasted in scenario analyses. Possible effect modifiers were diagnosis and glucocorticoid use.</p> <p>Results</p> <p>A total of 567 patients with requested neutrophil counts and 1,439 patients with non-requested neutrophil counts were analyzed. The absolute neutrophil count at admission differed with a mean of 7.4 × 10⁹/l for requested counts and 8.3 × 10⁹/l for non-requested counts (p-value < 0.001). This difference could be explained for 83.2% by the occurrence of cardiovascular disease as underlying disease and for 4.5% by glucocorticoid use.</p> <p>Conclusion</p> <p>Requests for neutrophil counts in clinical databases are associated with underlying disease and with cardiovascular disease in particular. The results from our study show the importance of evaluating testing bias in epidemiological studies obtaining data from clinical databases.</p

Про оцінку напружено-деформованого стану конвеєрної стрічки на дузі ковзання

Работа посвящена расширению сферы применения техники Л. Прандтля на решение задачи о взаимодействии конвейерной ленты и нефутерованного барабана. Получено решение задачи Ламе с соответствующими граничными условиями, что позволило выяснить характер деформаций на дуге скольжения. Приведены графики деформаций и соответствующих им напряжений.The paper is devoted to expand L. Prandtl technique to contact the conveyor belt with rigid drum. The Lamb task solving with corresponding boundary condition allow explaining the deflection nature in slide arch drum. The deflections and corresponding stresses graphics are demonstrated

Less discontinuation of ADHD drug use since the availability of long-acting ADHD medication in children, adolescents and adults under the age of 45 years in the Netherlands

Treatment options for ADHD in the Netherlands have increased with the introduction of the extended-release formulations of methylphenidate (MPH ER, Concerta®) in 2003 and atomoxetine (ATX, Strattera®) in 2005, but data on the effect on drug usage patterns are scarce. The objective of the present study was to describe changes in the patterns of ADHD medication use and determinants thereof among children, adolescents and adults (<45 years) starting ADHD medication since the introduction of MPH ER and ATX. Data were obtained from Dutch community pharmacies as collected by the Foundation for Pharmaceutical Statistics, covering 97% of all dispenses for prescription medicines to outpatients in the Netherlands. Usage patterns (continuation, discontinuation, switching and addition) of ADHD drugs were evaluated at 3, 6 and 12 months after initiation for three separate time cohorts (patients starting ADHD medication in Jan-Dec 2002, Jan 2003–June 2004, respectively July 2004–Dec 2005). It was found that between 2002 and 2006, most ADHD drug users were initiated on methylphenidate IR. Discontinuation of any ADHD drug treatment decreased over time partly in favour of switching and addition. Discontinuation at 3 months decreased from around 33% to around 25%, at 6 months from less than 50% to almost 35%, and at 12 months from just fewer than 60% to less than 45%. Discontinuation was higher among females and in adults >18 years. After the introduction of MPH ER and ATX (time cohort III), 16.5% of the incident ADHD drug users switched their medication and almost 9% added an ADHD drug to the prior ADHD drug. In conclusion, discontinuation of incident ADHD drug use is high after 3, 6 and 12 months. During the study period, the incidence of discontinuation decreased because of the availability of extended-release methylphenidate and atomoxetine

The association between prescription change frequency, chronic disease score and hospital admissions: a case control study

BACKGROUND: The aim of this study was to assess the association between prescription changes frequency (PCF) and hospital admissions and to compare the PCF to the Chronic Disease Score (CDS). The CDS measures comorbidity on the basis of the 1-year pharmacy dispensing data. In contrast, the PCF is based on prescription changes over a 3-month period. METHODS: A retrospective matched case–control design was conducted. 10.000 patients were selected randomly from the Dutch PHARMO database, who had been hospitalized (index date) between July 1, 1998 and June 30, 2000. The primary study outcome was the number of prescription changes during several three-month time periods starting 18, 12, 9, 6, and 3 months before the index date. For each hospitalized patient, one nonhospitalized patient was matched for age, sex, and geographic area, and was assigned the same index date as the corresponding hospitalized patient. We classified four mutually exclusive types of prescription changes: change in dosage, switch, stop and start. RESULTS: The study population comprised 8,681 hospitalized patients and an equal number of matched nonhospitalized patients. The odds ratio of hospital admission increased with an increase in PCF category. At 3 months before the index date from PCF=1 OR 1.4 [95% CI 1.3-1.5] to PCF= 2–3 OR 2.2 [95% CI 1.9-2.4] and to PCF ≥ 4 OR 4.1 [95% CI 3.1-5.1]. A higher CDS score was also associated with an increased odds ratio of hospitalization: OR 1.3 (95% CI 1.2-1.4) for CDS 3–4, and OR 3.0 (95% CI 2.7-3.3) for CDS 5 or higher. CONCLUSION: The prescription change frequency (PCF) is associated with hospital admission, like the CDS. Pharmacists and other healthcare workers should be alert when the frequency of prescription changes increases. Clinical rules could be helpful to make pharmacists and physicians aware of the risk of the number of prescription changes

Gastrointestinal toxicity among patients taking selective COX-2 inhibitors or conventional NSAIDs, alone or combined with proton pump inhibitors: a case-control study

PURPOSE: To assess the risk of gastrointestinal perforation, ulcers, or bleeding (PUB) associated with the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) with proton pump inhibitors (PPIs) and selective COX-2 inhibitors, with or without PPIs compared with conventional NSAIDs. METHODS: A case-control study was performed within conventional NSAIDs and/or selective COX-2 inhibitors users identified from the Dutch PHARMO Record Linkage System in the period 1998-2012. Cases were patients aged ≥18 years with a first hospital admission for PUB. For each case, up to four controls were matched for age and sex at the date a case was hospitalized (index date). Logistic regression analysis was used to calculate odds ratios (ORs). RESULTS: At the index date, 2634 cases and 5074 controls were current users of conventional NSAIDs or selective COX-2 inhibitors. Compared with conventional NSAIDs, selective COX-2 inhibitors with PPIs had the lowest risk of PUB (adjusted OR 0.51, 95% confidence interval [CI]: 0.35-0.73) followed by selective COX-2 inhibitors (adjusted OR 0.66, 95%CI: 0.48-0.89) and conventional NSAIDs with PPIs (adjusted OR 0.79, 95%CI: 0.68-0.92). Compared with conventional NSAIDs, the risk of PUB was lower for those aged ≥75 years taking conventional NSAIDs with PPIs compared with younger patients (adjusted interaction OR 0.79, 95%CI: 0.64-0.99). However, those aged ≥75 years taking selective COX-2 inhibitors, the risk was higher compared with younger patients (adjusted interaction OR 1.22, 95%CI: 1.01-1.47). CONCLUSIONS: Selective COX-2 inhibitors with PPIs, selective COX-2 inhibitors, and conventional NSAIDs with PPIs were associated with lower risks of PUB compared with conventional NSAIDs. These effects were modified by age. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd

Linking community pharmacy dispensing data to prescribing data of general practitioners

BACKGROUND: Databases are frequently used for pharmacoepidemiological research. However, most of these databases consist either of prescribing, dispensing or administrative data and therefore lack insight in the interaction between the several health professionals around the patient. METHODS: To determine the success rate of linking records from the dispensing database of the Foundation for Pharmaceutical Statistics to the prescribing database of the second Dutch national survey of general practice, conducted by NIVEL (Netherlands Institute for Health Services Research), a deterministic record linkage approach was used with patient and prescription characteristics as matching variables between the two databases. RESULTS: The catchment area included 123 community pharmacies, 90 GP practices and approximately 170,000 unique patients. Overall 110,102 (64.8%) unique patients were linked using the matching variables patient's gender, year of birth, the 4-digit part of the postal code, date of dispensing/prescribing and ATC-code. The final database contains of the 110,102 both prescribing data from 83 GP practices and dispensing data of 112 community pharmacies. CONCLUSION: This study shows that linkage of dispensing to prescribing data is feasible with a combination of patient characteristics, such as gender, year of birth and postal code, and prescription characteristics like prescription date and ATC-code. We obtained a linkage proportion of 64.8% resulting in complete prescribing and dispensing history of 110,102 patients. This offers an opportunity to gain insight in the mechanisms and factors influencing drug utilisation in general practice

Patterns of antiplatelet use in patients with myocardial infarction and subsequent acute coronary syndrome events

Background: Antiplatelet drugs are important for secondary prevention of cardiovascular events after myocardial infarction (MI). Objectives: The objectives of this study were to assess the patterns of antiplatelet drug use in patients who had a MI and to evaluate the impact of subsequent acute coronary syndrome (ACS) events on antiplatelet drug use in the Netherlands. Methods: A descriptive retrospective cohort study was conducted on 4719 patients in Utrecht Cardiovascular Pharmacogenetics studies, who had their first MI during 1986-2009. Medication use was assessed through the Dutch PHARMO Record Linkage System (dispensing database linked to the hospital admission registry). Antiplatelet users were classified as continuous users (gap between consecutive prescriptions ≤90 days), discontinued users (gap of >90days or no refills), and restarters (with a new antiplatelet drug episode after earlier discontinuation) and were followed for a maximum of 10years. Antiplatelet drug use in 90days before and after recurrent consecutive ACS events (MI and unstable angina) following the first MI was also compared. Results: At 1 year of follow-up, 83.7% patients continued using antiplatelets, 76.9% were still on aspirin, and only 36.4% patients were continuing clopidogrel. Most of the discontinuers restarted antiplatelet drugs later, leading to 74.7% antiplatelet users, 62.1% aspirin users and 35.2% clopidogrel users in 10 years after the index MI. For a subgroup of MI patients who started dual antiplatelet therapy with aspirin and clopidogrel (DAPT) after hospital discharge in 2002-2009, a total of 28.9% remained continuous users in 1 year, whereas 24% of the subjects switched to aspirin or clopidogrel monotherapy. When a recurrent ACS event occurred, antiplatelet use increased by 3.6% (

Recruitment failure and futility were the most common reasons for discontinuation of clinical drug trials. Results of a nationwide inception cohort study in the Netherlands

Objectives The objective of the study was to identify the reasons for discontinuation of clinical drug trials and to evaluate whether efficacy-related discontinuations were adequately planned in the trial protocol. Study Design and Setting All clinical drug trials in the Netherlands, reviewed by institutional review boards in 2007, were followed until December 2015. Data were obtained through the database of the Dutch competent authority (Central Committee on Research Involving Human Subjects [CCMO]) and a questionnaire to the principal investigators. Reasons for trial discontinuation were the primary outcome of the study. Three reasons for discontinuation were analyzed separately: all cause, recruitment failure, and efficacy related (when an interim analysis had demonstrated futility or superiority). Among the efficacy-related discontinuations, we examined whether the data monitoring committee, the stopping rule, and the moment of the interim analysis in the trial progress were specified in the trial protocol. Results Of the 574 trials, 102 (17.8%) were discontinued. The most common reasons were recruitment failure (33 of 574; 5.7%) and solely efficacy related (30 of 574; 5.2%). Of the efficacy-related discontinuations, 10 of 30 (33.3%) of the trial protocols reported all three aspects in the trial protocol, and 20 of 30 (66.7%) reported at least one aspect in the trial protocol. Conclusion One out of five clinical drug trials is discontinued before the planned trial end, with recruitment failure and futility as the most common reasons. The target sample size of trials should be feasible, and interim analyses should be adequately described in trial protocols

Impulse control disorders associated with dopaminergic drugs: A disproportionality analysis using vigibase

BACKGROUND: Dopamine receptor agonist drugs, which are used, for example, to treat Parkinson's disease (PD), increase the risk for impulse control disorders (ICDs), potentially resulting in devastating psychosocial consequences. It is unknown whether other drugs with dopaminergic properties also increase the risk for ICDs. This study assesses the disproportionality of reporting ICDs between drugs with dopaminergic properties and selected non-dopaminergic drugs. METHODS: A case/non-case disproportionality analysis was performed, using data from VigiBase (1968-2020). Reports on ICDs as suspected adverse drug reactions (ADRs) were cases (n=852), and those with ADRs other than ICDs were non-cases (n=281,720). Relative reporting frequencies were expressed as adjusted reporting odds ratios (aRORs). Within the dopamine receptor agonists, the relationship between reporting odds ratios and dopamine receptor occupancy was explored. RESULTS: A high disproportionality was found for reporting ICDs for all dopaminergic drugs (aROR 20.4 [95% CI 17.4-24.1]) compared to non-dopaminergic drugs. In pharmacotherapeutic subgroups, a high disproportionality was found for primary dopaminergic agents used in PD (aROR 52.1 [95% CI 44.1-61.5]), and to a lesser extent for ADHD psychostimulants and antidepressants (aROR 5.8 [95% 4.1-8.3] and aROR 3.9 [95% CI 2.9-5.6], respectively). There was no difference in reporting by consumers and healthcare professionals. The highest disproportionality was found for the dopamine receptor agonists pramipexole and ropinirole. CONCLUSIONS: A signal of disproportion in ICD occurrence was found among all investigated drugs with dopaminergic properties, highlighting the importance of counselling and monitoring for ICDs when prescribing dopaminergic drugs

Suspected adverse reactions reported for blood, blood components, and blood products in VigiBase

INTRODUCTION: Since being designated as medicines by World Health Organization (WHO), blood components are subject to pharmacovigilance reporting. Using VigiBase, the WHO global database of individual case safety reports (ICSRs), we characterized reports of adverse reactions for all blood products. STUDY DESIGN AND METHODS: ICSRs involving blood products as the suspected medicine in VigiBase between 1968 and 2021 were extracted. MedDRA preferred terms and the International Society of Blood Transfusion haemovigilance definitions were used to stratify adverse reactions. Descriptive statistics were used to characterize ICSR demographics. RESULTS: A total of 111,033 ICSRs containing 577,577 suspected adverse reactions with 6152 MedDRA preferred terms were reported for 34 blood products. There were 12,153 (10.9%) reports for blood components, 98,135 (88.4%) reports for plasma-derived medicines, and 745 (0.7%) reports for recombinant products. The majority of reports (21.0% and 19.7%, respectively) were from patients aged 45-64 and over 65 years. The Americas contributed the most ICSRs (49.7%). Top reported suspected adverse reactions were for the following MedDRA preferred terms: headache (3.5%), pyrexia (2.8%), chills (2.8%), dyspnoea (1.8%), and nausea (1.8%). CONCLUSION: VigiBase already has a large number of reports on blood products. When compared to other existing haemovigilance databases, our study found reports from a broader range of countries and reporters. This may provide us with new perspectives, but for VigiBase to reach its full potential in haemovigilance some alterations in what is captured in reports are required