How pharmacoepidemiology networks can manage distributed analyses to improve replicability and transparency and minimize bias

Several pharmacoepidemiology networks have been developed over the past decade that use a distributed approach, implementing the same analysis at multiple data sites, to preserve privacy and minimize data sharing. Distributed networks are efficient, by interrogating data on very large populations. The structure of these networks can also be leveraged to improve replicability, increase transparency, and reduce bias. We describe some features of distributed networks using, as examples, the Canadian Network for Observational Drug Effect Studies, the Sentinel System in the USA, and the European Research Network of Pharmacovigilance and Pharmacoepidemiology. Common protocols, analysis plans, and data models, with policies on amendments and protocol violations, are key features. These tools ensure that studies can be audited and repeated as necessary. Blinding and strict conflict of interest policies reduce the potential for bias in analyses and interpretation. These developments should improve the timeliness and accuracy of information used to support both clinical and regulatory decisions

Instrumental Variables in Influenza Vaccination Studies:Mission Impossible?!

AbstractObjectivesUnobserved confounding has been suggested to explain the effect of influenza vaccination on mortality reported in several observational studies. An instrumental variable (IV) is strongly related to the exposure under study, but not directly or indirectly (through other variables) with the outcome. Theoretically, analyses using IVs to control for both observed and unobserved confounding may provide unbiased estimates of influenza vaccine effects. We assessed the usefulness of IV analysis in influenza vaccination studies.MethodsInformation on patients aged 65 years and older from the computerized Utrecht General Practitioner (GP) research database over seven influenza epidemic periods was pooled to estimate the association between influenza vaccination and all-cause mortality among community-dwelling elderly. Potential IVs included in the analysis were a history of gout, a history of orthopaedic morbidity, a history of antacid medication use, and GP-specific vaccination rates.ResultsUsing linear regression analyses, all possible IVs were associated with vaccination status: risk difference (RD) 7.8% (95% confidence interval [CI] 3.6%; 12.0%), RD 2.8% (95% CI 1.7%; 3.9%), RD 8.1% (95% CI 6.1%; 10.1%), and RD 100.0% (95% CI 89.0%; 111.0%) for gout, orthopaedic morbidity, antacid medication use, and GP-specific vaccination rates, respectively. Each potential IV, however, also appeared to be related to mortality through other observed confounding variables (notably age, sex, and comorbidity).ConclusionsThe potential IVs studied did not meet the necessary criteria, because they were (indirectly) associated with the outcome. These variables may, therefore, not be suited to assess unconfounded influenza vaccine effects through IV analysis

Modelling approach to simulate reductions in LDL cholesterol levels after combined intake of statins and phytosterols/-stanols in humans

<p>Abstract</p> <p>Background</p> <p>To examine the effects on LDL cholesterol of the combined use of statins and phytosterols/-stanols, in vivo studies and clinical trials are necessary. However, for a better interpretation of the experimental data as well as to possibly predict cholesterol levels given a certain dosing regimen of statins and phytosterols/-stanols a more theoretically based approach is helpful. This study aims to construct a mathematical model to simulate reductions in low-density lipoprotein (LDL) cholesterol in persons who combine the use of statins with a high intake of phytosterols/-stanols, e.g. by the use of functional foods.</p> <p>Methods and Results</p> <p>The proposed model includes the cholesterol pool size in the liver and serum levels of very low-density lipoprotein (VLDL) cholesterol. Both an additional and a multiplicative effect of phytosterol/-stanol intake on LDL cholesterol reduction were predicted from the model. The additional effect relates to the decrease of dietary cholesterol uptake reduction, the multiplicative effect relates to the decrease in enterohepatic recycling efficiency, causing increased cholesterol elimination through bile. From the model, it was demonstrated that a daily intake of 2 g phytosterols/-stanols reduces LDL cholesterol level by about 8% to 9% on top of the reduction resulting from statin use. The additional decrease in LDL cholesterol caused by phytosterol/-stanol use at the recommended level of 2 g/d appeared to be similar or even greater than the decrease achieved by doubling the statin dose.</p> <p>Conclusion</p> <p>We proposed a simplified mathematical model to simulate the reduction in LDL cholesterol after separate and combined intake of statins and functional foods acting on intestinal (re)absorption of cholesterol or bile acids in humans. In future work, this model can be extended to include more complex (regulatory) mechanisms.</p

Пам'яті Миколи Чумаченка

14 жовтня на 87-ому році життя відійшов у вічність видатний учений-економіст, доктор економічних наук, академік Національної академії наук України, заслужений діяч науки і техніки України, лауреат Державної премії України в галузі науки і техніки, лауреат премій АН УРСР ім. О.Г. Шліхтера та НАН України ім. М.І. Тугана-Барановського, почесний директор Інституту економіки промисловості НАН України, ветеран Великої Вітчизняної війни, почесний громадянин міста Донецька голова редакційної колегії журналу Схід з економіки Микола Григорович Чумаченко

The risk of acute myocardial infarction associated with non-steroidal anti-inflammatory drugs users: Impact of additional confounding control for variables collected from self-reported data

Background: Several observational studies have employed electronic health databases to study the association between non-steroidal anti-inflammatory drugs (NSAIDs) and myocardial infarction. Because some important potential confounders might not be routinely collected in such data sources, patients' reports could be utilized additionally. Objectives: This study evaluated the impact of using additional information from patients' reports when assessing the association between use of NSAIDs and the risk of acute myocardial infarction (AMI). Methods: A case-control study was conducted among adult patients with hypertension and/or hypercholesterolemia in the Utrecht Cardiovascular Pharmacogenetics study. Information was collected from the Dutch PHARMO Database Network (Pharmacy and hospitalization records) and patients' questionnaires (body mass index, alcohol use, smoking, physical activity, and familial history of cardiovascular diseases). For each case, up to 13 controls were matched based on age and gender at the date cases were hospitalized (index date). Conditional logistic regression analysis was applied to estimate odd ratios (ORs) and 95% confidence intervals (95% CI). Results: We identified 970 AMI cases and 2,974 controls during 1985-2005. Of all cases, 140 patients (14.4%) were exposed to conventional NSAIDs and 9 patients (1.0%) were exposed to selective COX-2 inhibitors at the index date. Compared to nonuse, neither conventional NSAIDs [(Adj. OR 0.98, 95% CI: 0.91-1.06) nor selective COX-2 inhibitors (Adj. OR 1.00, 95% CI: 0.74- 1.36) were associated with an increased risk of AMI after adjustment for confounders routinely collected in pharmacy records. Additional adjustment for confounders collected from patients' reports did not change the risk estimates [(Adj. OR 0.97, 95% CI: 0.90-1.05) and (Adj. OR 1.01, 95% CI: 0.75- 1.35)], respectively. Conclusions: This study showed that additional potential confounders collected from patients' reports did not significantly change the risk estimates

Pharmacogenomic insights into treatment and management of statin-induced myopathy

Although statins are generally well tolerated, the most common adverse drug reaction from statin therapy is myopathy. This article reviews the current pharmacogenomic knowledge of statin-induced myopathy. Furthermore, we will discuss the importance of recent pharmacogenetic advances for the treatment and management of statin-induced myopathy. Variation in the SLCO1B1 gene is associated with increased incidence of statin-induced myopathy, particularly with simvastatin and less so with other statins. If different pharmacokinetic enzymes and transporters are responsible for susceptibility to myopathy, this may explain differences in the occurrence of statin-induced myopathy in individual patients. Genotyping in patients suffering from statin-induced myopathy may help to personalize the choice of statin for the lowest chance of developing myopathy

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% (

Коректність задачі Коші для нескінченної системи нелінійних осциляторів, розміщених на двовимірній решітці

Стаття присвячена вивченню нескінченної системи диференціальних рівнянь, яка описує нескінченний ланцюг лінійно зв’язаних нелінійних осциляторів. Отримано результати про існування та єдиність локального та глобального розв’язків задачі Коші.The article deals with infinite systems of differential equations that describe infinite system of nonlinear oscillators on 2D–lattice. It is obtained results on existence and uniqueness of local and global solutions to the Cauchy problem

Increasing the information provided by probabilistic sensitivity analysis:The relative density plot

Background Results of probabilistic sensitivity analyses (PSA) are frequently visualized as a scatterplot, which is limited through overdrawing and a lack of insight in relative density. To overcome these limitations, we have developed the Relative Density plot (PSA-ReD). Methods The PSA-ReD combines a density plot and a contour plot to visualize and quantify PSA results. Relative density, depicted using a color gradient, is transformed to a cumulative probability. Contours are then plotted over regions with a specific cumulative probability. We use two real-world case studies to demonstrate the value of the PSA-ReD plot. Results The PSA-ReD method demonstrates proof-of-concept and feasibility. In the real-world case-studies, PSA-ReD provided additional visual information that could not be understood from the traditional scatterplot. High density areas were identified by color-coding and the contour plot allowed for quantification of PSA iterations within areas of the cost-effectiveness plane, diminishing overdrawing and putting infrequent iterations in perspective. Critically, the PSA-ReD plot informs modellers about non-linearities within their model. Conclusions The PSA-ReD plot is easy to implement, presents more of the information enclosed in PSA data, and prevents inappropriate interpretation of PSA results. It gives modelers additional insight in model functioning and the distribution of uncertainty around the cost-effectiveness estimate