The Dutch Parelsnoer Institute Cerebrovascular Disease Initiative: a retrospective study of the effects of integrating clinical care and research on costs and quality of care in patients with ischaemic stroke.

INTRODUCTION: The Dutch Parelsnoer Institute (PSI) is a collaboration between all university medical centres in which clinical data, imaging and biomaterials are prospectively and uniformly collected for research purposes. The PSI has the ambition to integrate data collected in the context of clinical care with data collected primarily for research purposes. We aimed to evaluate the effects of such integrated registration on costs, efficiency and quality of care. METHODS: We retrospectively included patients with cerebral ischaemia of the PSI Cerebrovascular Disease Consortium at two participating centres, one applying an integrated approach on registration of clinical and research data and another with a separate method of registration. We determined the effect of integrated registration on (1) costs and time efficiency using a comparative matched cohort study in 40 patients and (2) quality of the discharge letter in a retrospective cohort study of 400 patients. RESULTS: A shorter registration time (mean difference of -4.6 min, SD 4.7, p=0.001) and a higher quality score of discharge letters (mean difference of 856 points, SD 40.8, p<0.001) was shown for integrated registration compared with separate registration. Integrated registration of data of 300 patients per year would save around €700 salary costs per year. CONCLUSION: Integrated registration of clinical and research data in patients with cerebral ischaemia is associated with some decrease in salary costs, while at the same time, increased time efficiency and quality of the discharge letter are accomplished. Thus, we recommend integrated registration of clinical and research data in centres with high-volume registration only, due to the initial investments needed to adopt the registration software.

The FAIR guiding principles for data stewardship: fair enough?

The FAIR guiding principles for research data stewardship (findability, accessibility, interoperability, and reusability) look set to become a cornerstone of research in the life sciences. A critical appraisal of these principles in light of ongoing discussions and developments about data sharing is in order. The FAIR principles point the way forward for facilitating data sharing more systematically-provided that a number of ethical, methodological, and organisational challenges are addressed as well.

A Stepwise Procedure to Define a Data Collection Framework for a Clinical Biobank.

INTRODUCTION: Current guidelines for clinical biobanking have a strong focus on obtaining, handling, and storage of biospecimens. However, to allow for research tying biomarker analysis to clinical decision making, there should be more focus on collection of data on donor characteristics. Therefore, our aim was to develop a stepwise procedure to define a framework as a tool to help start the data collection process in clinical biobanking. MATERIALS AND METHODS: The Radboud Biobank (RB) is a central clinical biobanking facility designed in accordance with the standards set by the Parelsnoer Institute, a Dutch national biobank originally initiated with eight different disease cohorts. To organize the information of these cohorts, we used our experience and knowledge in the field of biobanking and translational research to identify research domains and information categories to classify data. We extended this classification system to a stepwise procedure for defining a data collection framework and examined its utility for existing RB biobanks. RESULTS: Our approach resulted in the definition of a three-step procedure: (1) Identification of research domains and relevant questions within the field that may benefit from biobank samples. (2) Identification of information categories and accompanying subcategories that are relevant for answering questions in identified research domains. (3) Reduction to an efficient framework based on essentiality and quality criteria. We showed the utility of the procedure for three existing RB biobanks. DISCUSSION: We developed guidelines for the definition of a framework that supports the standardization of the biobank data collection process. Connecting the biobank database to pertinent information collected from the electronic health record will improve data quality and efficiency for both care and research. This is crucial when using the corresponding biospecimens for scientific research. Further, it also facilitates the combination of different clinical biobanks for a specific disease.

Patients to learn from: on the need for systematic integration of research and care in academic health care.

Patients suffering from rare, extreme or extremely complex sets of symptoms have something to expect from efforts to improve care through research. Biomedical research and care have often been approached as distinct worlds which are and should be only loosely connected. For observational research focusing on data drawn from real-world settings, however, that approach is found wanting. Integrating research and care responsibly is the main challenge instead. Integrated IT infrastructures facilitating Personalized medicine and Big Data are crucial components of a learning health care system, in which patients regularly play a double role: as individuals to be treated and as cases to learn from. Drawing on the example of the Dutch Parelsnoer Institute (PSI), a national biobanking and IT infrastructure integrated with clinical care procedures, this article outlines the reforms that are needed. Systematic integration of research and care offers a promising avenue, provided that a number of conditions are met: data and IT infrastructures will require overhauls in order to facilitate secure, high-quality data integration between research and care; institutional focus is needed to bring patient populations and expertise together; ethical frameworks and approaches for integrating research and care responsibly require further elaboration; clinical procedures and professional responsibilities may need to be adapted in order to accommodate research requirements in clinical processes; and involvement of patients and other stakeholders in design and research priority setting is needed to further the goals of real-world and patient relevance. RELEVANCE FOR PATIENTS: Integrating research and care in academic medicine in a more systematic fashion offers a promising perspective to current and future patients. In order to live up to these promises, research and care should be integrated more systematically in academic health science, with patients being included as research participants by default. Data and tissue infrastructures and facilities can provide a platform for doing so. At the same time, many issues remain to be settled. New ethical ways and means for protecting and respecting patient-participants in such a double role are also needed in this respect. In this way a deeper transformation is at stake as well: a change towards a setting in which patients fully take center stage in debate and action on the future of biomedicine.

Self management for patients with chronic obstructive pulmonary disease.

BACKGROUND: Self management interventions help patients with chronic obstructive pulmonary disease (COPD) acquire and practise the skills they need to carry out disease-specific medical regimens, guide changes in health behaviour and provide emotional support to enable patients to control their disease. Since the first update of this review in 2007, several studies have been published. The results of the second update are reported here. OBJECTIVES: 1. To evaluate whether self management interventions in COPD lead to improved health outcomes.2. To evaluate whether self management interventions in COPD lead to reduced healthcare utilisation. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (current to August 2011). SELECTION CRITERIA: Controlled trials (randomised and non-randomised) published after 1994, assessing the efficacy of self management interventions for individuals with COPD, were included. Interventions with fewer than two contact moments between study participants and healthcare providers were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Investigators were contacted to ask for additional information. When appropriate, study results were pooled using a random-effects model. The primary outcomes of the review were health-related quality of life (HRQoL) and number of hospital admissions. MAIN RESULTS: Twenty-nine studies were included. Twenty-three studies on 3189 participants compared self management versus usual care; six studies on 499 participants compared different components of self management on a head-to-head basis. Although we included non-randomised controlled clinical trials as well as RCTs in this review, we restricted the primary analysis to RCTs only and reported these trials in the abstract.In the 23 studies with a usual care control group, follow-up time ranged from two to 24 months. The content of the interventions was diverse. A statistically relevant effect of self management on HRQoL was found (St George's Respiratory Questionnaire (SGRQ) total score, mean difference (MD) -3.51, 95% confidence interval (CI) -5.37 to -1.65, 10 studies, 1413 participants, moderate-quality evidence). Self management also led to a lower probability of respiratory-related hospitalisation (odds ratio (OR) 0.57, 95% CI 0.43 to 0.75, nine studies, 1749 participants, moderate-quality evidence). Over one year of follow-up, eight (95% CI 5 to 14) participants with a high baseline risk of respiratory-related hospital admission needed to be treated to prevent one participant with at least one hospital admission, and 20 (95% CI 15 to 35) participants with a low baseline risk of hospitalisation needed to be treated to prevent one participant with at least one respiratory-related hospital admission.No statistically significant effect of self management on all-cause hospitalisation (OR 0.77, 95% CI 0.45 to 1.30, 6 studies, 1365 participants, low-quality evidence) or mortality (OR 0.79, 95% CI 0.58 to 1.07, 8 studies, 2134 participants, very low-quality evidence) was detected. Also, dyspnoea measured by the (modified) Medical Research Council Scale ((m)MRC) was reduced in individuals who participated in self management (MD -0.83, 95% CI -1.36 to -0.30, 3 studies, 119 participants, low-quality evidence). The difference in exercise capacity as measured by the six-minute walking test was not statistically significant (MD 33.69 m, 95% CI -9.12 to 76.50, 6 studies, 570 participants, very low-quality evidence). Subgroup analyses depending on the use of an exercise programme as part of the intervention revealed no statistically significant differences between studies with and without exercise programmes in our primary outcomes of HRQoL and respiratory-related hospital admissions.We were unable to pool head-to-head trials because of heterogeneity among interventions and controls; thus results are presented narratively within the review. AUTHORS' CONCLUSIONS: Self management interventions in patients with COPD are associated with improved health-related quality of life as measured by the SGRQ, a reduction in respiratory-related hospital admissions, and improvement in dyspnoea as measured by the (m)MRC. No statistically significant differences were found in other outcome parameters. However, heterogeneity among interventions, study populations, follow-up time and outcome measures makes it difficult to formulate clear recommendations regarding the most effective form and content of self management in COPD.

[Biobanks and the return of results to donors]. / Biobanken en de terugkoppeling van onderzoeksbevindingen aan donoren.

Biobanks should return clinically significant and actionable research findings to donors who have given physical material to the biobank. Because the clinical significance of a research finding is hard to determine for the individual donor, a procedure to decide on clinical significance should be incorporated into a structure for the actual feedback of research results. Most published studies show that donors expect return of individual research results, but there is almost no experience with it. Explorative questionnaire-based research among Dutch biobanks from the BioBanking Medical Research Infrastructure (BBMRI.NL) shows that a substantial group of biobanks can return individual research findings from data analysis. On the basis of these experiences a return of results policy may be drafted that answers to the interests of donors and the possibilities of biobanks.

Rationale and design of the PRegnancy and Infant DEvelopment (PRIDE) Study.

BACKGROUND: To optimise the health of pregnant women and their children by evidence-based primary and secondary prevention, more scientific knowledge is needed. To overcome the methodological limitations of many studies on pregnancy and child health, which often use a retrospective design, we established the PRIDE (PRegnancy and Infant DEvelopment) Study. METHODS AND RESULTS: The PRIDE Study is a large prospective cohort study that aims at including 150 000-200 000 women in early pregnancy to study a broad range of research questions pertaining to pregnancy complications, maternal and child health, and adverse developmental effects in offspring. Women are invited to participate by their prenatal care provider before or at their first prenatal care visit and are asked to fill out web-based questionnaires in gestational weeks 8-10, 17, and 34, as well as biannually throughout childhood. In addition, a food frequency questionnaire and a paternal questionnaire are administered and medical records are consulted. Multiple validation studies will be conducted and paper-and-pencil questionnaires are available for women who cannot or do not want to participate through the Internet. For subgroups of participants, blood and saliva samples for genetic and biochemical analyses are being collected. The pilot phase, which started in July 2011, showed a response rate of 47%. Recruitment will eventually cover all of the Netherlands. CONCLUSIONS: We expect that this study, which will be the largest birth cohort in the world so far, will provide new insights in the aetiology of disorders and diseases that originate in pregnancy. The PRIDE Study is open for collaboration.

Cancer in adolescents and young adults (15-29 years): a population-based study in the Netherlands 1989-2009.

BACKGROUND: Cancer among adolescents and young adults (AYAs; 15-29 years old) is relatively rare but its incidence is increasing worldwide. To define the extent and nature of the AYA patients, this population-based study was performed to explore trends in cancer incidence, survival and risk of second primary cancers in AYAs. MATERIAL AND METHODS: Data from all AYAs diagnosed with cancer between 1989 and 2009 were obtained from the Netherlands Cancer Registry. Age-standardized incidence rates with estimated annual percentage of change (EAPC) and five-year relative survival rates were calculated. Relative survival was used as a good approximation of cause-specific survival. All analyses were stratified by gender, five-year age group and calendar period. In addition, Standardized Incidence Ratios were determined to evaluate the risk of second primary cancers. RESULTS: 23 161 AYAs were diagnosed with cancer between 1989 and 2009. Since 1989 the cancer incidence has increased significantly from 28 to 43 per 100 000 person years in males (EAPC: 1.9) and from 30 to 40 per 100 000 person years in females (EAPC: 1.4). The most frequently diagnosed cancers in male AYAs included testicular cancer, melanoma and Hodgkin's disease, whereas in females melanoma, breast cancer and Hodgkin's disease were the most frequently occurring cancers. Five-year relative survival rates were 80% and 82% for males and females, respectively. Over time, the five-year relative survival increased from 74% to 86% and from 79% to 86% in males and females, respectively. The risk of developing a second primary cancer was increased three to six times in males and two to five times in females, depending on rules for counting second primary cancers. CONCLUSIONS: Although the overall survival has improved over time, the progress made in AYAs for specific cancers is still less compared to improvements made in children and adults. This and the increasing incidence and high risk of second primary cancers warrants further research.

Excellent adherence and no contamination by physiotherapists involved in a randomized controlled trial on reactivation of COPD patients: a qualitative process evaluation study.

OBJECTIVE: To assess the adherence of physiotherapists to the study protocol and the occurrence of contamination bias during the course of a randomized controlled trial with a recruitment period of 2 years and a 1-year follow-up (COPE-II study). STUDY DESIGN AND SETTING: In the COPE-II study, intervention patients received a standardized physiotherapeutic reactivation intervention (COPE-active) and control patients received usual care. The latter could include regular physiotherapy treatment. Information about the adherence of physiotherapists with the study protocol was collected by performing a single interview with both intervention and control patients. Patients were only interviewed when they were currently receiving physiotherapy. Interviews were performed during two separate time periods, 10 months apart. Nine characteristics of the COPE-active intervention were scored. Scores were converted into percentages (0%, no aspects of COPE-active; 100%, full implementation of COPE-active). RESULTS: Fifty-one patients were interviewed (first period: intervention n = 14 and control n = 10; second period: intervention n = 18 and control n = 9). Adherence with the COPE-active protocol was high (median scores: period 1, 96.8%; period 2, 92.1%), and large contrasts in scores between the intervention and control group were found (period 1: 96.8% versus 22.7%; period 2: 92.1% versus 25.0%). The scores of patients treated by seven physiotherapists who trained patients of both study groups were similar to the scores of patients treated by physiotherapists who only trained patients of one study group. CONCLUSION: The adherence of physiotherapists with the COPE-active protocol was high, remained unchanged over time, and no obvious contamination bias occurred.

Risk factors for undescended testis.

OBJECTIVE: To contribute to the understanding of the etiology of undescended testis (UDT), by exploring a wide range of potential risk factors in a case-referent study. PATIENTS AND METHODS: Cases and referents were recruited at five hospitals and included 200 boys with surgically corrected UDT and 629 boys with persistent middle ear effusion. Risk factor data were obtained by postal questionnaires to both parents. Clinical data were collected from medical files. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: The main findings include associations between UDT and familial occurrence of the disorder: OR 3.1 (95%CI 1.9-4.9), low birth weight: 2.2 (1.1-4.3), twinning: 2.2 (0.9-5.4), gestational preeclampsia: 1.9 (0.8-4.4), use of oral contraceptives after conception: 3.6 (1.0-12.5), in vitro fertilization/intracytoplasmic sperm injection treatment: 2.2 (0.8-6.0), paternal subfertility: 1.8 (0.8-4.1), and maternal occupational exposure to cosmetics: 3.0 (0.9-10.0). Subgroup analyses indicated differences in ORs for several factors between cases with (n = 92) and without (n = 103) inguinal hernia or hydrocele. CONCLUSION: The findings point towards a role for genetic predisposition, placental insufficiency, and possibly exposure to specific endocrine disrupting substances in the etiology of UDT. Further research should take into account potential etiologic differences between subgroups of cases with UDT.

Weight of in vitro fertilization and intracytoplasmic sperm injection singletons in early childhood.

Birth weight and longitudinal growth in the first 4 years of life of term singletons conceived with the use of IVF and intracytoplasmic sperm injection (ICSI) were compared with those of naturally conceived singletons. Although IVF and ICSI singletons had a statistically significantly lower birth weight than naturally conceived singletons, the average individual weight curves showed that this difference was lost before the age of 4 years in all subgroups: IVF, ICSI, boys, and girls.

Teratogenic mechanisms of medical drugs.

BACKGROUND Although prescription drug use is common during pregnancy, the human teratogenic risks are undetermined for more than 90% of drug treatments approved in the USA during the past decades. A particular birth defect may have its origins through multiple mechanisms and possible exposures, including medications. A specific pathogenic process may result in different outcomes depending upon factors such as embryonic age at which a drug is administered, duration and dose of exposure and genetic susceptibility. This review focuses on the teratogenic mechanisms associated with a number of medications. METHODS We used three methods to identify the teratogenic mechanisms of medications: the MEDLINE and EMBASE databases, two recent books on teratogenic agents and a list of drugs classified as U.S. Food and Drug Administration class D or X. Mechanisms were included only if they are associated with major structural birth defects and medications that are used relatively frequently by women of reproductive age. RESULTS We identified six teratogenic mechanisms associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption and specific receptor- or enzyme-mediated teratogenesis. Many medications classified as class X are associated with at least one of these mechanisms. CONCLUSIONS Identifying teratogenic mechanisms may not only be relevant for etiologic and post-marketing research, but may also have implications for drug development and prescribing behavior for women of reproductive age, especially since combinations of seemingly unrelated prescription and over the counter medications may utilize similar teratogenic mechanisms with a resultant increased risk of birth defects.

Fatigue and chronic fatigue syndrome-like complaints in the general population.

BACKGROUND: Most knowledge on chronic fatigue (CF) and chronic fatigue syndrome (CFS) is based on clinical studies, not representative of the general population. This study aimed to assess the prevalence of fatigue in an adult general population and to identify associations with lifestyle factors. METHODS: Total 22,500 residents of Nijmegen were selected at random and interviewed by questionnaire. Data on 9062 respondents (43% response) were analysed, taken into account age, gender and concomitant disease. Subjects were classified into four groups: not fatigued (NF, reference group), short-term fatigue (SF, <6 months), chronic fatigue (CF, >or=6 months) and CFS-like fatigue (in accordance with the Center for Disease Control criteria for CFS, without clinical confirmation). RESULTS: Our study population showed the following breakdown: NF 64.4% (95% CI 63.6-65.6%), SF 4.9% (95% CI 4.5-5.4%), CF 30.5% (95% CI 29.5-31.4%) and CFS-like fatigue 1.0% (95% CI 0.8-1.2%). Compared with the NF group, more of the CFS respondents were female [odds ratio (OR) = 1.9], obese (OR = 4.1), using analgesics (OR = 7.8), had a low alcohol intake (OR = 0.4), were eating less healthy food (OR = 0.5) and were physically less active (OR = 0.1). These associations largely applied to the SF and CF group. The fatigue could have been due to a concomitant disease in 34 and 55.5% of the SF and CF cases, respectively. CONCLUSION: The prevalence of CF in the general population appears to be much higher than previously indicated. Even with strict criteria for CFS, it is estimated that approximately 1% of the adult population experiences this condition. Interestingly, a large part of this group remains unrecognized by the general practitioner. A striking similarity in lifestyle pattern between SF, CF and CFS calls for further research.

Hypospadias: risk factor patterns and different phenotypes.

OBJECTIVE: To obtain more insight into the origin of hypospadias by exploring a wide range of potential risk factors in a case-referent study in which a distinction was made between different phenotypes. PATIENTS AND METHODS: Cases and referents were 305 boys with hypospadias and 629 boys with middle ear effusion whose parents completed postal questionnaires. Hypospadias phenotype was classified as distal (195 boys), middle (67), and proximal (43). Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Low birth weight, being a twin or triplet, mother being a diethylstilbestrol-daughter, fertility treatments, paternal subfertility, obesity, prescriptive drug use, and familial occurrence of hypospadias or testicular cancer were associated with hypospadias in general. For familial occurrence of hypospadias, there were high risk estimates for the distal and middle phenotypes with an OR (95%CI) of 10.4 (4.5-24.1) and 9.0 (3.1-26.0), but not for the proximal type at 1.8 (0.2-14.9). By contrast, the association with low birth weight (a proxy for placental dysfunction) seemed much stronger for proximal hypospadias with an OR (95%CI) of 9.1 (3.4-24.2) compared with distal and middle hypospadias at 2.6 (1.4-5.0) and 2.3 (0.8-6.5). There were similar estimates for pre-eclampsia. CONCLUSION: These findings indicate aetiological heterogeneity of hypospadias and provide indications for the possible mechanisms through which specific risk factors may interfere with penile development.

Definitions of exacerbations: does it really matter in clinical trials on COPD?

Many definitions of COPD exacerbations are reported. The choice for a definition determines the number of exacerbations observed. However, the effect of different definitions on the effect sizes of randomized controlled trials is unclear. This article provides an overview of the large variation of definitions of COPD exacerbations from the literature. Furthermore, the effect of using different definitions on effect sizes (relative risk and hazard ratio) was investigated in a randomized controlled discontinuation trial of inhaled corticosteroids. The following definitions were applied: (1) unscheduled medical attention, (2) a course of oral corticosteroids/antibiotics, (3) deterioration in two major or one major and one minor symptom according to Anthonisen (referenced later), (4) a change in one or more symptoms, (5) a change in two or more symptoms, and (6) a combination of numbers 2 and 4. Relative risks for the exacerbation rate ranged from 1.19 to 1.49, and hazard ratios for time to first exacerbation ranged from 1.36 to 1.84 for the various definitions, varying from nonsignificant to significant. Because the definition of a COPD exacerbation has an impact on the effect size of interventions, there is an urgent need for concerted attempts to reach agreement on a definition of an exacerbation. Also, the exact definition to be used in a study should be specified in the protocol.

Sonotubometry in children with otitis media with effusion before and after insertion of ventilation tubes.

OBJECTIVES: To test the outcome of sonotubometric measurement in children with otitis media with effusion (OME) before and after insertion of ventilation tubes. DESIGN: Eustachian tube ventilatory function was tested in children with OME. To test validity, sonotubometric testing took place before insertion of ventilation tubes (ie, glue ear) and 1 week and 3 months after grommet insertion (ie, aerated middle ear cavity). One set of measurements consisted of 10 acts of swallowing. The outcomes of the tests were compared with those in otologically healthy controls. SETTINGS: All testing took place during an outpatient clinic otorhinolaryngologic consultation in a city hospital. PATIENTS: Thiry-three children with OME and 61 otologically healthy children (controls). INTERVENTIONS: Surgical grommet insertion. MAIN OUTCOME MEASURES: Sonotubometric measurements before and after insertion of ventilation tubes. RESULTS: Fewer incidences of the opening of the eustachian tube were recorded in the measurements before insertion of ventilation tubes compared with after insertion. The number of incidences of opening recorded after insertion of ventilation tubes did not significantly differ from measurements in healthy controls. CONCLUSIONS: Sonotubometric testing in children with OME reveals a low incidence of eustachian tube opening. Shortly after insertion of ventilation tubes, sonotubometry revealed no difference in eustachian tube ventilatory function compared with measurements in healthy controls. The low incidence of eustachian tube opening before grommet insertion may be attributable to decreased opening or dampening of the sound transmission by the middle ear fluid.

Striking trends in the incidence of health problems in The Netherlands (2002-05). Findings from a new strategy for surveillance in general practice.

BACKGROUND: This study aimed to detect striking trends based on a new strategy for monitoring public health. METHODS: We used data over 4 years from electronic medical records of a large, nationally representative network of general practices. Episodes were either directly recorded by general practitioners (GPs) or were constructed using a new record linkage method (EPICON). The episodes were used to estimate raw morbidity rates for all codes of the International Classification of Primary Care (ICPC). Multilevel Poisson regression models were used to analyse the trend over time for 15 health problems that showed an obvious change over time. Based on these models, we calculated adjusted incidence rates corrected for clustering, sex and age. RESULTS: During 2002-05, both men and women increasingly consulted the GP because of concern about a drug reaction, a change in faeces/bowel movements and urination problems. Men showed an increase in consultations for prostate problems and venereal diseases. The incidence of chronic internal knee derangement decreased for both sexes. Women consulted their GP less frequently about sterilization and fear of being pregnant. CONCLUSION: The strategy developed proved to be useful to detect trends across a short period of time. Changes in the health care market, such as the increasing availability of over-the-counter drugs and various large advertising campaigns for medications may explain some of the findings. The increasing incidence of health problems in the urogenital area deserves attention as it could reflect increases in the incidence of sexually transmitted diseases (STDs) and urinary tract infections.

Decreasing incidence of adenotonsillar problems in Dutch general practice: real or artefact?

BACKGROUND: The incidence of hypertrophy and recurrent infections of the tonsils/adenoids appears to be decreasing in the Netherlands. It is uncertain whether this is a 'real' decrease in the incidence of disease or an 'artefact'. AIM: To investigate possible causes of the decreasing incidence of adenotonsillar problems among Dutch children. DESIGN OF STUDY: Observational. SETTING: A nationally representative general practice database. METHOD: Incidence rates were calculated over 2002-2005 among children aged 0-14 years. Multilevel Poisson regression analyses were used to examine the following possible causes of changing incidence rates: change in recording (more substitution codes), change in the demand for care (fewer visits to the GP), and change in the supply of care (fewer antibiotic prescriptions and referrals). Indications for a 'real' change in the incidence of disease were examined by calculating incidence rates of other clinical manifestations of microbial pathogens that may cause adenotonsillar problems. RESULTS: The incidence rate decreased significantly (P = 0.017) from 3.0 to 1.3 per 1000 children per year. Correcting for demand for and supply of care led to a smaller decline in yearly incidence, from 2.9 to 1.7 per 1000 children per year (P = 0.105). No clearly similar trend was found in other clinical manifestations of viruses and bacteria that may cause adenotonsillar problems. CONCLUSION: Part of the declining trend can be explained by a change in the demand for and supply of care, but no apparent causal clue emerged for the residual declining trend in the incidence of disease.

Publication bias was not a good reason to discourage trials with low power.

OBJECTIVE: The objective was to investigate whether it is justified to discourage trials with less than 80% power. Trials with low power are unlikely to produce conclusive results, but their findings can be used by pooling then in a meta-analysis. However, such an analysis may be biased, because trials with low power are likely to have a nonsignificant result and are less likely to be published than trials with a statistically significant outcome. STUDY DESIGN AND SETTING: We simulated several series of studies with varying degrees of publication bias and then calculated the "real" one-sided type I error and the bias of meta-analyses with a "nominal" error rate (significance level) of 2.5%. RESULTS: In single trials, in which heterogeneity was set at zero, low, and high, the error rates were 2.3%, 4.7%, and 16.5%, respectively. In multiple trials with 80%-90% power and a publication rate of 90% when the results were nonsignificant, the error rates could be as high as 5.1%. When the power was 50% and the publication rate of non-significant results was 60%, the error rates did not exceed 5.3%, whereas the bias was at most 15% of the difference used in the power calculation. CONCLUSION: The impact of publication bias does not warrant the exclusion of trials with 50% power.

External validation of EPICON: a grouping system for estimating morbidity rates using electronic medical records.

OBJECTIVE: To externally validate EPICON, a computerized system for grouping diagnoses from EMRs in general practice into episodes of care. These episodes can be used for estimating morbidity rates. DESIGN: Comparative observational study. MEASUREMENTS: Morbidity rates from an independent dataset, based on episode-oriented EMRs, were used as the gold standard. The EMRs in this dataset contained diagnoses which were manually grouped by GPs. The authors ungrouped these diagnoses and regrouped them automatically into episodes using EPICON. The authors then used these episodes to estimate morbidity rates that were compared to the gold standard. The differences between the two sets of morbidity rates were calculated and the authors analyzed large as well as structural differences to establish possible causes. RESULTS: In general, the morbidity rates based on EPICON deviate only slightly from the gold standard. Out of 675 diagnoses, 36 (5%) were considered to be deviating diagnoses. The deviating diagnoses showed differences for two main reasons: "differences in rules between the two methods of episode construction" and "inadequate performance of EPICON." CONCLUSION: The EPICON system performs well for the large majority of the morbidity rates. We can therefore conclude that EPICON is useful for grouping episodes to estimate morbidity rates using EMRs from general practices. Morbidity rates of diseases with a broad range of symptoms should, however, be interpreted cautiously.