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The use of retrospective health care claims datasets is frequently criticized for the lack of complete information on potential confounders. Utilizing patient’s health status–related information from claims datasets as surrogates or proxies for mismeasured and unobserved confounders, the high-dimensional propensity score algorithm enables us to reduce bias. Using a previously published cohort study of postmyocardial infarction statin use (1998–2012), we compare the performance of the algorithm with a number of popular machine learning approaches for confounder selection in high-dimensional covariate spacesrandom forest, least absolute shrinkage and selection operator, and elastic net. Our results suggest that, when the data analysis is done with epidemiologic principles in mind, machine learning methods perform as well as the high-dimensional propensity score algorithm. Using a plasmode framework that mimicked the empirical data, we also showed that a hybrid of machine learning and high-dimensional propensity score algorithms generally perform slightly better than both in terms of mean squared error, when a bias-based analysis is used.

In this analysis of data from several large cohorts of patients with diabetes, antidiabetic incretin-based drugs were not associated with an increased risk of hospitalization for heart failure, as compared with commonly used combinations of oral antidiabetic drugs. The safety of incretin-based drugs, which include dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, is controversial. Although much attention has been focused on adverse pancreatic events, there are new concerns about an increased risk of heart failure. 1 Indeed, in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, 2 , 3 patients who were randomly assigned to the DPP-4 inhibitor saxagliptin had a 27% increase in the risk of hospitalization for heart failure as compared with those who received placebo. In contrast, the Examination of Cardiovascular Outcomes with . . .

Gestational diabetes mellitus (GDM) increases the risk of early-onset type 2 diabetes, which further exacerbates the risk of developing diabetic complications such as kidney, circulatory, and neurological complications. Yet, existing models have solely focused on the prediction of type 2 diabetes, and not of its complications, which are arguably the most clinically relevant outcomes. Our aim was to develop a prediction model for type 2 diabetic complications in patients with GDM. Using provincial administrative data from Quebec, Canada, we developed a model to predict type 2 diabetic complications within 10 years among 90,143 women with GDM. The model was internally validated and assessed for discrimination, calibration, and risk stratification accuracy. The incidence of diabetic complications was 3.8 (95% confidence interval (CI) 3.4–4.3) per 10,000 person-years. The final prediction model included maternal age, socioeconomic deprivation, substance use disorder, gestational age at delivery, severe maternal morbidity, previous pregnancy complications, and hypertensive disorders of pregnancy. The model had good discrimination [area under the curve (AUROC) 0.72 (95% CI 0.69–0.74)] and calibration (slope ≥ 0.9) to predict diabetic complications. In the highest category of the risk stratification table, the positive likelihood ratio was 8.68 (95% CI 4.14–18.23), thereby showing a moderate ability to identify women at highest risk of developing type 2 diabetic complications. Our model predicts the risk of type 2 diabetic complications with moderate accuracy and, once externally validated, may prove to be a useful tool in the management of women after GDM.

Subclinical hypothyroidism has been linked to adverse renal outcomes, but it is unknown whether treatment of subclinical hypothyroidism reduces the risk of these adverse outcomes. We sought to assess whether treatment of subclinical hypothyroidism with levothyroxine is associated with a decreased risk of developing adverse renal outcomes. We conducted a population-based cohort study using a prevalent new-user design. Using the Clinical Practice Research Datalink in the United Kingdom, we assembled a study cohort of individuals aged 18 years and older with newly diagnosed subclinical hypothyroidism between 1998 and 2018. We matched individuals with subclinical hypothyroidism treated with levothyroxine to nontreated individuals with subclinical hypothyroidism based on age, sex, calendar time, duration of subclinical hypothyroidism, and time-conditional propensity score. We included several confounders, including data on demographics, clinical diagnoses, biochemical measures, lifestyle, and prescriptions, in the time-conditional propensity score estimate. The primary outcome was a composite end point of end-stage renal disease (requiring dialysis) and lowering of the estimated glomerular filtration rate of 50% or greater. We matched 76 697 individuals with subclinical hypothyroidism treated with levothyroxine to 76 697 nontreated individuals. The mean age of the study cohort was 63 years, and 77% of patients were female. During a median follow-up time of 1.6 years (levothyroxine treated: 1.0, interquartile range [IQR] 0.4–2.7, yr; nontreated: 2.5, IQR 0.9–5.7, yr), 2426 adverse renal events occurred among nontreated individuals (incidence rate 8.35, 95% confidence interval [CI] 8.02–8.69, per 1000 person-years), and 1255 adverse renal events occurred among levothyroxine-treated individuals (incidence rate 7.93, 95% CI 7.50–8.39, per 1000 person-years). Treatment with levothyroxine was not associated with the risk of adverse renal outcomes among people with subclinical hypothyroidism (adjusted hazard ratio 0.97, 95% CI 0.90–1.04). In this population-based cohort study, there was no evidence that levothyroxine treatment of subclinical hypothyroidism reduced the risk of adverse renal outcomes. Future studies in different populations and with longer duration of follow-up are needed to confirm these findings.

Background: We sought to determine the association between maternal vitamin D status at ≤26 weeks' gestation and the risk of preeclampsia by clinical subtype. Methods: We conducted a case–cohort study among women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project. In serum collected at ≤26 weeks' gestation (median 20.9 weeks) from 717 women who later developed preeclampsia (560 mild and 157 severe cases) and from 2986 mothers without preeclampsia, we measured serum 25-hydroxyvitamin D, over 40 years later, using liquid chromatography–tandem mass spectrometry. Results: Half of women in the subcohort had 25-hydroxyvitamin D (25(OH)D) >50 nmol/L. Maternal 25(OH)D 50 to 74.9 nmol/L was associated with a reduction in the absolute and relative risk of preeclampsia and mild preeclampsia compared with 25(OH)D <30 nmol/L in the crude analysis but not after adjustment for confounders, including race, prepregnancy body mass index, and parity. For severe preeclampsia, 25(OH)D ≥50 nmol/L was associated with a reduction in three cases per 1000 pregnancies (adjusted risk difference = −0.003 [95% confidence interval = −0.005 to 0.0002]) and a 40% reduction in risk (0.65 [0.43 to 0.98]) compared with 25(OH) D <50 nmol/L. Conclusions were unchanged (1) after restricting to women with 25(OH)D measured before 22 weeks' gestation or (2) with formal sensitivity analyses for unmeasured confounding. Conclusions: Maternal vitamin D deficiency may be a risk factor for severe preeclampsia but not for its mild subtypes. Contemporary cohorts with large numbers of severe preeclampsia cases would be needed to confirm or refute these findings.

Abstract Rationale Unreported exacerbations and failure to seek medical attention may have consequences on the health of patients with chronic obstructive pulmonary disease. Objectives This study aims to determine the incidence of reported and unreported exacerbations, to identify predictors of reporting, and to compare the impact of reported and unreported exacerbations on health status. Methods The study is based on a multicenter Canadian cohort of patients with chronic obstructive pulmonary disease. Measurements and Main Results Patients completed a daily diary from which exacerbations were defined as a worsening of at least one key symptom (dyspnea, sputum amount, sputum color) recorded on at least 2 consecutive days. Patients were asked to contact the study center if there was a sustained worsening of symptom. Reported exacerbations were events that led to contacting study center or health care visit. The study enrolled 421 patients. The overall incidence of diary exacerbations was 2.7 per person per year, but only 0.8 per person per year was reported. Predictors of reporting included age (HR [hazard ratio], 0.90; 95% confidence interval [CI], 0.81–0.98 per 5-yr increase), FEV1% predicted (HR, 0.84; 95% CI, 0.70–0.99 per 10% increase), number of symptoms at onset (HR, 1.59; 95% CI, 1.37–1.84 per additional symptom), and time of the week (HR, 0.35; 95% CI, 0.22–0.56 weekend vs. weekday). There was a clinically important decline in health status for 52% of patients with reported exacerbation and 43% with unreported exacerbations. Conclusions This study has shown that less than one-third of the exacerbations were reported. The number of symptoms at onset was the most important predictor of reporting an exacerbation, and both reported and unreported exacerbations had an impact on health status.

Objective To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes.Design Population based cohort.Setting Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom.Participants A cohort of 972 384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014.Main outcome measures Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models.Results During 2 024 441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking.Conclusions In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the latency of the cancer, these findings provide some reassurance on the safety of incretin based drugs.

Abstract Rationale Depression and anxiety are significant comorbid and potentially modifiable conditions in chronic obstructive pulmonary disease (COPD), but their effects on exacerbations are not clear. Objectives To investigate the independent effect of depression and anxiety on the risk of COPD exacerbations and hospitalizations. Methods A multicenter prospective cohort study in 491 patients with stable COPD in China. Multivariate Poisson and linear regression analyses were used, respectively, to estimate adjusted incidence rate ratios (IRRs) and adjusted effects on duration of events. Measurements and Main Results Depression and anxiety were measured using the Hospital Anxiety and Depression Scale (HADS) at baseline. Other measurements included sociodemographic, clinical, psychosocial, and treatment characteristics. Patients were then monitored monthly for 12 months to document the occurrence and characteristics of COPD exacerbations and hospitalizations. Exacerbation was determined using both symptom-based (worsening of ≥1 key symptom) and event-based definitions (≥1 symptom worsening plus ≥1 change in regular medications). A total of 876 symptom-based and 450 event-based exacerbations were recorded, among which 183 led to hospitalization. Probable depression (HADS depression score ≥ 11) was associated with an increased risk of symptom-based exacerbations (adjusted IRR, 1.51; 95% confidence interval [CI], 1.01–2.24), event-based exacerbations (adjusted IRR, 1.56; 95% CI, 1.02–2.40), and hospitalization (adjusted IRR, 1.72; 95% CI, 1.04–2.85) compared with nondepression (score ≤ 7). The duration of event-based exacerbations was 1.92 (1.04–3.54) times longer for patients with probable anxiety (HADS anxiety score ≥ 11) than those with no anxiety (score ≤ 7). Conclusions This study suggests a possible causal effect of depression on COPD exacerbations and hospitalizations. Further studies are warranted to confirm this finding and to test the effectiveness of antidepressants and psychotherapies on reducing exacerbations and improving health resource utilizations.

In 2019, the International Working Group (IWG), focusing on New Developments in Pharmacovigilance, was established. This group is coordinated by the Drug Safety Research Unit in the United Kingdom, and the mission of the IWG is to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines, thereby further protecting patients. Novel therapeutics are continuously being developed to alleviate medical conditions, but with advancing technologies, innovative pharmacovigilance methodologies need to be developed to effectively monitor the use and safety of these products. With reduced timelines proposed for premarketing clinical trials and increased application of real-world evidence supporting regulatory approvals, products may be used in real-world clinical practice in shorter timeframes than before. Therefore, the need for effective methods of monitoring medicines and collecting safety data in real-time is of paramount importance to public health. The IWG aims to advance existing methodologies used in the detection, monitoring, and analysis of safety data in pharmacovigilance and to communicate best practice proposals to support decision making in health care. The IWG will identify areas requiring review of current processes or methodologic research and will communicate the output of the IWG through peer-reviewed publications, reports, and presentation of findings at relevant conferences and scientific meetings. The IWG is currently reviewing two areas in pharmacovigilance; case-level causality assessment and the strengths and limitations of data sources. The IWG is advancing these areas by producing two scoping reviews which will be easily accessible to regulatory agencies, industry, academia, and interested persons or organizations. The scoping reviews comply with the IWGs mission to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines. The present article shares details of the objectives of the IWG and provides an overview on the status of IWG activities.

ObjectivesTo describe the impact of the COVID-19 pandemic on hypertension diagnosis and management in UK primary care.DesignPopulation-based cohort study.SettingOver 2000 general practices across the UK contributing to the Clinical Practice Research Datalink.ParticipantsA cohort of 23 076 390 patients over 18 years of age and registered with their general practice for at least 1 year between 2011 and 2022, who did not have a previous diagnosis of hypertension. From these patients, a subcohort of 712 461 patients diagnosed with hypertension between 2011 and 2022 was selected.Primary and secondary outcome measuresCoprimary outcomes included rates of hypertension diagnosis and rates of antihypertensive treatment initiation, treatment change and blood pressure measurement in patients newly diagnosed with hypertension.ResultsIn April 2020, the first month of lockdown, incident hypertension diagnosis rates fell by 65% (95% CI 64% to 67%) compared with historical trends and remained depressed until November 2021, leading to 51 000 fewer diagnoses than expected by March 2022. However, by March 2022, there were 2.6% fewer diagnoses than expected in Scotland, compared with 20%–30% fewer in other UK Nations. Rates of treatment initiation and change fell by 47% (95% CI 43% to 51%) and 36% (95% CI 33% to 38%), respectively, in April 2020. However, initiation rates rebounded above expectations and remained elevated until March 2022. Blood pressure measurements fell by 69% (95% CI 65% to 72%) in April 2020, recovering in February 2021.ConclusionsHypertension diagnosis and management in UK primary care were significantly disrupted during the COVID-19 pandemic. Future studies should investigate the potential clinical implications for the cardiovascular health of the UK population.