Interactive exploration of population scale pharmacoepidemiology datasets

Population-scale drug prescription data linked with adverse drug reaction (ADR) data supports the fitting of models large enough to detect drug use and ADR patterns that are not detectable using traditional methods on smaller datasets. However, detecting ADR patterns in large datasets requires tools for scalable data processing, machine learning for data analysis, and interactive visualization. To our knowledge no existing pharmacoepidemiology tool supports all three requirements. We have therefore created a tool for interactive exploration of patterns in prescription datasets with millions of samples. We use Spark to preprocess the data for machine learning and for analyses using SQL queries. We have implemented models in Keras and the scikit-learn framework. The model results are visualized and interpreted using live Python coding in Jupyter. We apply our tool to explore a 384 million prescription data set from the Norwegian Prescription Database combined with a 62 million prescriptions for elders that were hospitalized. We preprocess the data in two minutes, train models in seconds, and plot the results in milliseconds. Our results show the power of combining computational power, short computation times, and ease of use for analysis of population scale pharmacoepidemiology datasets. The code is open source and available at: https://github.com/uit-hdl/norpd_prescription_analyse

Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability

Importance: Women with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain. Objective: To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders. Design, Setting, and Participants: The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848). Exposures: Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth. Main Outcomes and Measures: We estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID). Results: A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital. Conclusions and Relevance: In this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevelopmental disorders.publishedVersio

Cancer risk among insulin users : comparing analogues with human insulin in the CARING five-country cohort study

Aims/hypothesis The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. Methods National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2010) and Sweden (2007-2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. Results A total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for 6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences. Conclusions/interpretation The present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years.Peer reviewe

Antipsychotic drug use in pregnancy: A multinational study from ten countries

Aim: To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents. Methods: Individually linked health data in Denmark (2000−2012), Finland (2005–2014), Iceland (2004–2017), Norway (2005–2015), Sweden (2006–2015), Germany (2006–2015), Australia (New South Wales, 2004–2012), Hong Kong (2001–2015), UK (2006–2016), and the US (Medicaid, 2000–2013, and IBM MarketScan, 2012–2015) were used. Using a uniformed approach, we estimated the prevalence of antipsychotic use as the proportion of pregnancies where a woman filled at least one antipsychotic prescription within three months before pregnancy until birth. For the Nordic countries, data were meta-analyzed to investigate maternal characteristics associated with the use of antipsychotics. Results: We included 8,394,343 pregnancies. Typical antipsychotic use was highest in the UK (4.4%) whereas atypical antipsychotic use was highest in the US Medicaid (1.5%). Atypical antipsychotic use increased over time in most populations, reaching 2% in Australia (2012) and US Medicaid (2013). In most countries, prochlorperazine was the most commonly used typical antipsychotic and quetiapine the most commonly used atypical antipsychotic. Use of antipsychotics decreased across the trimesters of pregnancy in all populations except Finland. Antipsychotic use was elevated among smokers and those with parity ≥4 in the Nordic countries. Conclusion: Antipsychotic use during pregnancy varied considerably between populations, partly explained by varying use of the typical antipsychotic prochlorperazine, which is often used for nausea and vomiting in early pregnancy. Increasing usage of atypical antipsychotics among pregnant women reflects the pattern that was previously reported for the general population

Does present use of cardiovascular medication reflect elevated cardiovascular risk scores estimated ten years ago? A population based longitudinal observational study

Background It is desirable that those at highest risk of cardiovascular disease should have priority for preventive measures, eg. treatment with prescription drugs to modify their risk. We wanted to investigate to what extent present use of cardiovascular medication (CVM) correlates with cardiovascular risk estimated by three different risk scores (Framingham, SCORE and NORRISK) ten years ago. Methods Prospective logitudinal observational study of 20 252 participants in The Hordaland Health Study born 1950-57, not using CVM in 1997-99. Prescription data obtained from The Norwegian Prescription Database in 2008. Results 26% of men and 22% of women aged 51-58 years had started to use some CVM during the previous decade. As a group, persons using CVM scored significantly higher on the risk algorithms Framingham, SCORE and NORRISK compared to those not treated. 16-20% of men and 20-22% of women with risk scores below the high-risk thresholds for the three risk scores were treated with CVM, while 60-65% of men and 25-45% of women with scores above the high-risk thresholds received no treatment. Among women using CVM, only 2.2% (NORRISK), 4.4% (SCORE) and 14.5% (Framingham) had risk scores above the high-risk values. Low education, poor self-reported general health, muscular pains, mental distress (in females only) and a family history of premature cardiovascular disease correlated with use of CVM. Elevated blood pressure was the single factor most strongly predictive of CVM treatment. Conclusion Prescription of CVM to middle-aged individuals by large seems to occur independently of estimated total cardiovascular risk, and this applies especially to females

Time-averaged disease activity fits better joint destruction in rheumatoid arthritis

Pathophysiology and treatment of rheumatic disease

Antipsychotic drug use in pregnancy: A multinational study from ten countries

Aim: To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents

Use of medications by people with chronic fatigue syndrome and healthy persons: a population-based study of fatiguing illness in Georgia

<p>Abstract</p> <p>Background</p> <p>Chronic fatigue syndrome (CFS) is a debilitating condition of unknown etiology and no definitive pharmacotherapy. Patients are usually prescribed symptomatic treatment or self-medicate. We evaluated prescription and non-prescription drug use among persons with CFS in Georgia and compared it to that in non-fatigued <it>Well </it>controls and also to chronically <it>Unwell </it>individuals not fully meeting criteria for CFS.</p> <p>Methods</p> <p>A population-based, case-control study. To identify persons with possible CFS-like illness and controls, we conducted a random-digit dialing telephone screening of 19,807 Georgia residents, followed by a detailed telephone interview of 5,630 to identify subjects with CFS-like illness, other chronically <it>Unwell</it>, and <it>Well </it>subjects. All those with CFS-like illness (n = 469), a random sample of chronically <it>Unwell </it>subjects (n = 505), and <it>Well </it>individuals (n = 641) who were age-, sex-, race-, and geographically matched to those with CFS-like illness were invited for a clinical evaluation and 783 participated (48% overall response rate). Clinical evaluation identified 113 persons with CFS, 264 <it>Unwell </it>subjects with insufficient symptoms for CFS (named ISF), and 124 <it>Well </it>controls; the remaining 280 subjects had exclusionary medical or psychiatric conditions, and 2 subjects could not be classified. Subjects were asked to bring all medications taken in the past 2 weeks to the clinic where a research nurse viewed and recorded the name and the dose of each medication.</p> <p>Results</p> <p>More than 90% of persons with CFS used at least one drug or supplement within the preceding two weeks. Among users, people with CFS used an average of 5.8 drugs or supplements, compared to 4.1 by ISF and 3.7 by <it>Well </it>controls. Persons with CFS were significantly more likely to use antidepressants, sedatives, muscle relaxants, and anti-acids than either <it>Well </it>controls or the ISF group. In addition, persons with CFS were significantly more likely to use pain-relievers, anti-histamines and cold/sinus medications than were <it>Well </it>controls.</p> <p>Conclusion</p> <p>Medical care providers of patients with chronic fatigue syndrome should be aware of polypharmacy as a problem in such patients, and the related potential iatrogenic effects and drug interactions.</p