Overcoming ethical and legal obstacles to data linkage in health research: stakeholder perspectives.

Introduction: Data linkage for health research purposes enables the answering of countless new research questions, is said to be cost effective and less intrusive than other means of data collection. Nevertheless, health researchers are currently dealing with a complicated, fragmented, and inconsistent regulatory landscape with regard to the processing of data, and progress in health research is hindered. Aim: We designed a qualitative study to assess what different stakeholders perceive as ethical and legal obstacles to data linkage for health research purposes, and how these obstacles could be overcome. Methods: Two focus groups and eighteen semi-structured in-depth interviews were held to collect opinions and insights of various stakeholders. An inductive thematic analysis approach was used to identify overarching themes. Results: This study showed that the ambiguity regarding the 'correct' interpretation of the law, the fragmentation of policies governing the processing of personal health data, and the demandingness of legal requirements are experienced as causes for the impediment of data linkage for research purposes by the participating stakeholders. To remove or reduce these obstacles authoritative interpretations of the laws and regulations governing data linkage should be issued. The participants furthermore encouraged the harmonisation of data linkage policies, as well as promoting trust and transparency and the enhancement of technical and organisational measures. Lastly, there is a demand for legislative and regulatory modifications amongst the participants. Conclusions: To overcome the obstacles in data linkage for scientific research purposes, perhaps we should shift the focus from adapting the current laws and regulations governing data linkage, or even designing completely new laws, towards creating a more thorough understanding of the law and making better use of the flexibilities within the existing legislation. Important steps in achieving this shift could be clarification of the legal provisions governing data linkage by issuing authoritative interpretations, as well as the strengthening of ethical-legal oversight bodies.

Effect and cost-effectiveness of step-up versus step-down treatment with antacids, H2-receptor antagonists, and proton pump inhibitors in patients with new onset dyspepsia (DIAMOND study): a primary-care-based randomised controlled trial.

BACKGROUND: Substantial physician workload and high costs are associated with the treatment of dyspepsia in primary health care. Despite the availability of consensus statements and guidelines, the most cost-effective empirical strategy for initial management of the condition remains to be determined. We compared step-up and step-down treatment strategies for initial management of patients with new onset dyspepsia in primary care. METHODS: Patients aged 18 years and older who consulted with their family doctor for new onset dyspepsia in the Netherlands were eligible for enrolment in this double-blind, randomised controlled trial. Between October, 2003, and January, 2006, 664 patients were randomly assigned to receive stepwise treatment with antacid, H(2)-receptor antagonist, and proton pump inhibitor (step-up; n=341), or these drugs in the reverse order (step-down; n=323), by use of a computer-generated sequence with blocks of six. Each step lasted 4 weeks and treatment only continued with the next step if symptoms persisted or relapsed within 4 weeks. Primary outcomes were symptom relief and cost-effectiveness of initial management at 6 months. Analysis was by intention to treat (ITT); the ITT population consisted of all patients with data for the primary outcome at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00247715. FINDINGS: 332 patients in the step-up, and 313 in the step-down group reached an endpoint with sufficient data for evaluation; the main reason for dropout was loss to follow-up. Treatment success after 6 months was achieved in 238 (72%) patients in the step-up group and 219 (70%) patients in the step-down group (odds ratio 0.92, 95% CI 0.7-1.3). The average medical costs were lower for patients in the step-up group than for those in the step-down group (euro228 vs euro245; p=0.0008), which was mainly because of costs of medication. One or more adverse drug events were reported by 94 (28%) patients in the step-up and 93 (29%) patients in the step-down group. All were minor events, including (other) dyspeptic symptoms, diarrhoea, constipation, and bad/dry taste. INTERPRETATION: Although treatment success with either step-up or step-down treatment is similar, the step-up strategy is more cost effective at 6 months for initial treatment of patients with new onset dyspeptic symptoms in primary care.

Renin-angiotensin system polymorphisms and the association between use of angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors and the risk of diabetes.

INTRODUCTION: We assessed the influence of genetic polymorphisms in the renin-angiotensin system on the risk of diabetes associated with the use of angiotensin II receptor blockers and angiotensin-converting enzyme (ACE) inhibitors. MATERIALS AND METHODS: We performed a matched case-control study among antihypertensive drug users. Pharmacy records and questionnaires were used to ascertain incident diabetes (cases), antihypertensive drug use, and risk factors. Controls did not (yet) have diabetes.We genotyped ACE (G4656C, which is in complete linkage disequilibrium with the ACE insertion/deletion polymorphism), angiotensinogen (M235T), and angiotensin II type 1 receptor (A1166C). RESULTS: Among 495 cases of incident diabetes and 2,624 controls, homozygous 1166C carriers of angiotensin II type 1 receptor who used angiotensin II receptor blockers had an increased risk of diabetes compared to 1166A carriers (interaction odds ratio 5.3 [95% confidence interval: 1.8-16.1]). Homozygous ACE GG subjects who used ACE inhibitors >or= 1 defined daily dose/day had a higher risk of diabetes compared to subjects with the ACE C allele (interaction odds ratio 2.3 [95% confidence interval: 1.2-4.5]). CONCLUSIONS: Angiotensin II receptor blockers increase the occurrence of diabetes in homozygous 1166C carriers of angiotensin II type 1 receptor, but not in 1166A carriers. ACE inhibitors at doses >or= 1 defined daily dose/day increase the risk of diabetes among homozygous ACE GG carriers, but not in 4656C carriers.

The relevance of health related quality of life in paced patients.

With the tremendous advances in cardiac pacing during the past four decades, cardiac pacemaker implantation is now a common clinical procedure. In recent years, the indications for permanent pacemakers have expanded. This increase in reasons for pacing and shift in mode of pacing have been caused by the evolution of pacemaker therapy from a life-saving measure (mortality), to one aimed at improving health-related quality of life (HRQoL). Until now the efficacy of pacing therapy has predominantly been measured using "objective" criteria. However, in recent years the importance of HRQoL as an outcome measure has increasingly been recognized as patients prefer quality over quantity of life. In this review we describe the development and testing of Aquarel, a new developed HRQoL questionnaire for pacemaker patients, composed of a generic core module with disease specific add-ons. Current and future research to improve the Aquarel questionnaire is also described.

Quitting smoking may restore hematological characteristics within five years.

PURPOSE: To describe the cross-sectional association of counts of total and subtypes of leukocytes, platelets, and selected characteristics of red blood cells with intensity of cigarette smoking and smoking cessation. METHODS: The study population consisted of 16,254 men and women 20-70 years of age who participated in the Dutch European Prospective Investigation into Cancer and nutrition (EPIC) subcohort, 1995-1997. Linear regression analysis was performed, for both sexes separately, to study the relation between various measurements of smoking habits and hematologic characteristics. RESULTS: Among current smokers, in both genders, packyears and daily number of cigarettes were associated with increased leukocytes (6-19%), lymphocytes (4-14%), monocytes (3-9%), neutrophils (7-24%), platelets (1-5%), mean corpuscular volume (0.4-2%), hematocrit (0.3-4%), hemoglobin (0.3-4%), and mean corpuscular hemoglobin (0.8-2%). In subjects who had quit smoking within two years before blood measurement, hematological characteristics in most cells were similar as in never smokers, whereas normal counts of lymphocytes and monocytes were observed only 2-5 years after quitting. CONCLUSIONS: Our findings suggest a marked influence of current smoking habits on leukocyte counts and, to a lesser extent, on counts of erythrocytes and platelets. Following smoking cessation, at least five years have to pass before changes in all hematological parameters may return to normal values.

Methods to assess intended effects of drug treatment in observational studies are reviewed.

BACKGROUND AND OBJECTIVE: To review methods that seek to adjust for confounding in observational studies when assessing intended drug effects. METHODS: We reviewed the statistical, economical and medical literature on the development, comparison and use of methods adjusting for confounding. RESULTS: In addition to standard statistical techniques of (logistic) regression and Cox proportional hazards regression, alternative methods have been proposed to adjust for confounding in observational studies. A first group of methods focus on the main problem of nonrandomization by balancing treatment groups on observed covariates: selection, matching, stratification, multivariate confounder score, and propensity score methods, of which the latter can be combined with stratification or various matching methods. Another group of methods look for variables to be used like randomization in order to adjust also for unobserved covariates: instrumental variable methods, two-stage least squares, and grouped-treatment approach. Identifying these variables is difficult, however, and assumptions are strong. Sensitivity analyses are useful tools in assessing the robustness and plausibility of the estimated treatment effects to variations in assumptions about unmeasured confounders. CONCLUSION: In most studies regression-like techniques are routinely used for adjustment for confounding, although alternative methods are available. More complete empirical evaluations comparing these methods in different situations are needed.

Prospective double-blind preoperative pain clinic screening before microsurgical denervation of the spermatic cord in patients with testicular pain syndrome.

Testicular pain syndrome (TPS), defined as an intermittent or constant pain in one or both testicles for at least 3 months, resulting in significant reduction of daily activities, is common. Microsurgical denervation of the spermatic cord (MDSC) has been suggested as an effective treatment option. The study population comprised 180 TPS patients admitted to our outpatient urology clinic between 1999 and 2011. On 3 different occasions, patients were offered a double-blind, placebo-controlled temporary blockade of the spermatic cord. A single blockade consisted of 10 mL 2% lidocaine, 10 mL 0.25% bupivacaine, or 10 mL 0.9% sodium chloride. If the results of these blockades were positive, MDSC was offered. All MDSCs were performed by a single urologist (M.T.W.T.L.) using an inguinal approach. Pain reduction was determined at prospective follow-up. This study evaluated 180 patients. Most patients (61.1%) had undergone a scrotal or inguinal procedure. Patients had complaints during sexual activities (51.7%), sitting (37.5%), and/or cycling (36.7%); 189 randomized blockades were offered to all patients. There was a positive response in 37% and a negative response in 51%. MDSC was performed on 58 testicular units, including 3 patients with a negative outcome of the blockades. At mean follow-up of 42.8 months, 86.2% had a ≥ 50% reduction of pain and 51.7% were completely pain free. MDSC is a valuable treatment option for TPS patients because in this study 86.2% experienced a ≥ 50% reduction of pain. To prevent superfluous diagnostics and treatment, it is mandatory to follow a systematic protocol in the treatment of TPS.

Escherichia coli bacteriuria in female adults is associated with the development of hypertension.

OBJECTIVE: To investigate whether Escherichia coli bacteriuria is associated with the development of hypertension during a long-term follow-up. METHODS: A prospective cohort study was performed among the participants of two population-based studies. Between 1974 and 1986 all women aged 39 to 68 years old, who lived in Utrecht, the Netherlands, were invited to participate in a breast cancer screening program. The participants completed a questionnaire, underwent a medical examination, and collected a morning urine sample that remained stored. From 1993 to 1997 another population-based study was performed. We performed a full cohort analysis for 444 women who participated in both studies. E. coli bacteriuria was diagnosed by a real-time PCR. Hypertension was defined as the use of antihypertensive medication and/or a measured systolic blood pressure of at least 160 mmHg or a diastolic blood pressure of 95 mmHg or higher. The mean follow-up was 11.5+/-1.7 years. RESULTS: Forty women (9%) had E. coli bacteriuria at baseline. Women who had bacteriuria at baseline had a mean blood pressure at study endpoint of 133+/-20 mmHg systolic and 78+/-11 mmHg diastolic, and women without bacteriuria had values of 129+/-20 and 78+/-11 mmHg, respectively (p-values for difference 0.33 and 0.88). Although E. coli bacteriuria was not associated with the blood pressure as a continuous variable, it was associated with the development of hypertension during follow-up (OR 2.8, 95% CI 1.4-5.5). CONCLUSION: E. coli bacteriuria may increase the risk of future hypertension.

Variation in Renin-Angiotensin system and salt-sensitivity genes and the risk of diabetes mellitus associated with the use of thiazide diuretics.

BACKGROUND: Variation in the renin-angiotensin system (RAS) and salt-sensitivity genes may influence the effect of thiazides on the risk of diabetes. We assessed whether polymorphisms in RAS and salt-sensitivity genes influenced the risk of diabetes associated with thiazides. METHODS: Nested case-control study was conducted among antihypertensive drug users. Pharmacy records and questionnaires were used to assess new onset diabetes (cases), to ascertain antihypertensive use and risk factors for diabetes. Cases were matched to controls (up to five) who were not (yet) diagnosed with diabetes mellitus. We genotyped angiotensin-converting enzyme (ACE) (G4656C), angiotensinogen (AGT) (M235T), angiotensin II type 1 receptor, (AGTR1) (A1166C), adducin 1 (alpha) (ADD1) (G460T), guanine nucleotide binding protein (G protein), beta-polypeptide 3 (GNB3) (C825T). RESULTS: Among 497 incident cases of type 2 diabetes and 2,633 controls, AGTR1 CC genotype carriers had no increased risk of diabetes due to thiazides (odds ratio (OR) 0.63 (95% confidence interval (CI): 0.28-1.40)) compared to AGTR1 1166A allele carriers (OR 1.79 (95% CI: 1.43-2.23)) receiving thiazides (synergy index (SI) for interaction 0.32 (95% CI: 0.15-0.68)). Although homozygous ACE GG subjects and ACE C allele carriers both had an increased risk of diabetes associated with thiazide use, this risk was more increased for ACE GG subjects (SI 1.70 (95% CI: 1.08-2.66)), particularly at doses > or =1 daily defined dose (DDD) (=25 mg hydrochlorothiazide)/day (SI 2.0 (95% CI: 1.20-3.32)). Among GNB3 T allele carriers, the risk of diabetes due to thiazide use was less increased than among homozygous GNB3 CC subjects (SI 0.62 (95% CI: 0.41-0.93)). CONCLUSION: The risk of diabetes due to thiazide use was not increased among AGTR1 1166 CC homozygous subjects and less increased among GNB3 T allele carriers. The ACE 4656 GG genotype enhanced the risk of diabetes due to thiazides.

High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides.

AIMS: High cholesteryl ester transfer protein (CETP) concentrations are associated with increased risk of cardiovascular disease (CVD) in subjects with high triglycerides. We determined the relationship of plasma CETP with incident CVD in a population with relatively low triglycerides. METHODS AND RESULTS: A nested case-control study was performed in men participating in the prospective PREVEND study, after exclusion of CVD, diabetes mellitus, and lipid-lowering drugs use at baseline. Plasma CETP was measured in 111 men who developed a cardiovascular event (cases) during follow-up and in 116 controls who remained free of CVD. Fasting total cholesterol (P < 0.001) and triglycerides (P < 0.001) were higher, HDL cholesterol was lower (P = 0.001), but CETP was similar in cases and controls (P = 0.39). Cox proportional hazards regression analysis showed that CVD risk tended to be lower with higher plasma CETP after adjustment for age and lipids (hazard ratio 0.84; 95% CI 0.69-1.03, P = 0.10). Plasma CETP was lower in cases than in controls (P = 0.05) with triglycerides < or = 1.38 mmol/L (median), but not with higher triglycerides. The age-adjusted hazard ratio for CVD was 0.46 (95% CI 0.24-0.90) in men with triglycerides < or = 1.38 mmol/L and CETP > 2.26 mg/L (median) compared with men with similarly low triglycerides and CETP < or = 2.26 mg/L. With higher triglycerides, the hazard ratio for CVD was similar in both CETP categories. CONCLUSION: Relatively high plasma CETP may favour reduced CVD risk in the context of low triglycerides.