Biobanking for epidemiology.

Biobanks are a key resource in unravelling the association between genetic background, lifestyle and environmental determinants of the incidence, natural course and treatment response for various complex diseases and health traits. Biobanks are goldmines for epidemiological research, provided that they are set up properly, enable multicentre collaboration, and are available for use by all serious epidemiology groups.

A multi-faceted strategy to improve the use of national fertility guidelines; a cluster-randomized controlled trial.

BACKGROUND Proper use of clinical practice guidelines can decrease variation in care between settings. However, actual use of fertility guidelines is suboptimal and in need of improvement. Hence, a cluster-randomized controlled trial was designed to study the effects of two strategies to implement national Dutch guidelines on comprehensive fertility care. METHODS Sixteen fertility clinics participated in the trial. A minimal, professional-oriented implementation strategy of audit and feedback was tested versus a maximal multi-faceted strategy that was both professional and patient oriented. The extent of adherence to guideline recommendations, reflected in quality indicator scores, was the primary outcome measure. To gain an insight into unwanted side effects, patient anxiety and depression scores were gathered as secondary outcomes. Data collection encompassed medical record search, patient and professional questionnaires. RESULTS A total of 1499 couples were included at baseline and 1396 at the after-measurement. No overall significant improvement in indicator scores was found for either strategy [odds ratios ranging from 0.23 (95% confidence interval (CI): 0.06-0.95) to 6.66 (95% CI: 0.33-132.8]. Secondary outcomes did not differ significantly for both groups, although selected anxiety scores appeared lower in the maximal intervention group. Process evaluation of the trial revealed positive patient experiences with the intervention material [e.g. an increased understanding of their doctor's treatment policy (61%), an increased ability to ask questions about the treatment (61%)]. Professionals' appreciation of intervention elements varied, and execution of the multi-faceted strategy appeared incomplete. DISCUSSION Absence of an intervention effect may be due to the nature of the strategies, incomplete execution or flaws in study design. Process evaluation data raise the question of whether professionals should be the only stakeholder responsible for guideline implementation. This study therefore contributes to an increased understanding of fertility guideline implementation in general, and the role of patients in particular.

Antihypertensive treatment during pregnancy and functional development at primary school age in a historical cohort study.

OBJECTIVE: To determine the functional development of children born after treatment of mild-to-moderate gestational hypertension with labetalol versus methyldopa, and no antihypertensive treatment. DESIGN: Historical cohort study. SETTING: Twelve Dutch hospital departments of obstetrics. POPULATION: Live-born children born in these hospitals and prenatally exposed to labetalol, methyldopa, or bed rest because of mild-to-moderate gestational hypertension. METHODS: Central nervous system development was measured with standard tests at 4-10 years of age. Linear regression techniques and Pearson's chi-square tests were used to compare the groups with regard to the outcome measures. MAIN OUTCOME MEASURES: Intelligence quotient (IQ), concentration, motor development, and behaviour at primary school age. RESULTS: A total of 202 children were included in the analyses. More children exposed to labetalol had attention deficit hyperactivity disorder (ADHD) than those exposed to methyldopa (OR 2.3; 95% CI 0.7-7.3), or those born to women who had been admitted for bed rest (OR 4.1; 95% CI 1.2-13.9). Sleeping problems seemed to be reported more frequently after prenatal methyldopa exposure than after exposure to labetalol (OR 3.2; 95% CI 0.6-16.7) or bed rest (OR 4.5; 95% CI 0.9-23.2), although the differences were not statistically significant. Test scores on other aspects of functional development did not differ between the three groups. CONCLUSIONS: In this hypothesis-generating study, labetalol exposure in utero seemed to increase the risk of ADHD among children of primary school age, whereas prenatal methyldopa exposure might influence sleep. Further studies with appropriate sample sizes are warranted to determine the long-term effects of antihypertensive medications.

Variation in subfertility care measured by guideline-based performance indicators.

BACKGROUND: About 30-40% of patients do not receive care based on available scientific evidence. For subfertility, this may imply unnecessary and expensive diagnostic tests and treatments. It is therefore important to identify gaps in performance by monitoring current subfertility care. A set of 39 guideline-based performance indicators was previously developed for this purpose. This study aimed to assess several quality criteria of the indicator-set and to use the set to assess current subfertility care. METHODS: A historic cohort study was performed in 16 Dutch subfertility clinics; 2698 couples were invited to participate. Indicator data were gathered by medical record extraction, and patient and professional questionnaires. Quality criteria for each indicator (measurability, reliability, applicability, improvement potential, discriminatory capacity, complexity and case-mix stability) were assessed. Current practice was measured as adherence to the separate indicators. RESULTS: One thousand four-hundred and ninety-nine (56%) couples participated. All indicators were measurable, but the results for the other quality criteria varied. In total, 14 of the 39 indicators scored <50% adherence. Variation in performance between the clinics was up to 100%. The highest median adherence (86%) is found within the guideline 'indications for IVF-treatment'. The lowest median adherence is found within the guideline 'initial assessment of fertility' (43%), followed closely by the guideline 'anovulation' (44%). CONCLUSIONS: This study shows the quality of the developed indicator-set for monitoring clinical subfertility care. A first assessment in the Netherlands reveals large variation between clinics and ample room for improvement of care.

Prognosis and vascular co-morbidity in dementia a historical cohort study in general practice.

BACKGROUND: Disease management of dementia in general practice (GP) is hampered by a lack of data on the prognosis of dementia. AIM: To gain more insight into the life expectancy of and the effects of cardiovascular and cerebrovascular co-morbidity in dementia patients in GP. DESIGN OF STUDY: Historical cohort. SETTING: 4 general practices in Nijmegen, The Netherlands. POPULATION: All patients in these practices participating in the Continuous Morbidity Registration (CMR). METHODS: The patient cohort was diagnosed with dementia between January 1st 1985 and December 31st 2002. The control cohort consisted of patients matched one-to-one with demented patients on age, sex, and socio-economic status. Cardiovascular and cerebrovascular co-morbidity was studied from 5 years before the diagnosis of dementia till the endpoints of data collection. RESULTS: 251 couples of patients and controls were formed (79 men, 172 women, mean age 81.4+/-7.0 years). The median life expectancy after diagnosis was 2.3 years for the dementia patients, and 3.7 years for the controls. Median time from diagnosis till nursing home placement was 1.4 years. Cerebrovascular and cardiovascular morbidity preceding dementia diagnosis decreased survival of cases with dementia with a relative risk of 1.54 (95%CI: 1.13-2.09) and in controls with a relative risk of 1.91 (95%CI: 1.48-2.46). Obesity was associated with a lower risk of dementia (RR=0.77 (95%-CI 0.63-0.94)). Hypertension and obesity diagnosed after the dementia diagnosis were significantly associated with an increase in survival. CONCLUSION: In general practice, the diagnosis of dementia is made at a late stage, when patients will continue to live at home only for a short time. Moreover, life expectancy at diagnosis is very limited and prognosis is furthermore negatively influenced by preceding cardio- and cerebrovascular co-morbidity.

Estimating morbidity rates from electronic medical records in general practice. Evaluation of a grouping system.

OBJECTIVES: In this study, we evaluated the internal validity of EPICON, an application for grouping ICPC-coded diagnoses from electronic medical records into episodes of care. These episodes are used to estimate morbidity rates in general practice. METHODS: Morbidity rates based on EPICON were compared to a gold standard; i.e. the rates from the second Dutch National Survey of General Practice. We calculated the deviation from the gold standard for 677 prevalence and 681 incidence rates, based on the full dataset. Additionally, we examined the effect of case-based reasoning within EPICON using a comparison to a simple, not case-based method (EPI-0). Finally, we used a split sample procedure to evaluate the performance of EPICON. RESULTS: Morbidity rates that are based on EPICON deviate only slightly from the gold standard and show no systematic bias. The effect of case-based reasoning within EPICON is evident. The addition of case-based reasoning to the grouping system reduced both systematic and random error. Although the morbidity rates that are based on the split sample procedure show no systematic bias, they do deviate more from the gold standard than morbidity rates for the full dataset. CONCLUSIONS: Results from this study indicate that the internal validity of EPICON is adequate. Assuming that the standard is gold, EPICON provides valid outcomes for this study population. EPICON seems useful for registries in general practice for the purpose of estimating morbidity rates.

Self-management education for patients with chronic obstructive pulmonary disease.

BACKGROUND: There is great interest in chronic obstructive pulmonary disease (COPD) and the associated large burden of disease. COPD is characterised by frequent day by day fluctuations, and repetitive clinical exacerbations are typical. Self-management is a term applied to educational programmes aimed at teaching skills needed to carry out medical regimens specific to the disease, guide health behaviour change, and provide emotional support for patients to control their disease and live functional lives. In COPD, the value of self-management education is not yet clear. The first Cochrane review about self-management was published in 2003. It was intended to shed light on the effectiveness of self-management programmes in COPD and the relative efficacy of their constitutive elements. No conclusions about the effectiveness of self-management could be drawn because of the large variation in outcome measures used in the limited number of included studies. This article describes the first update of this review. OBJECTIVES: The objective of this review was to assess the settings, methods and efficacy of COPD self-management education programmes on health outcomes and use of health care services. SEARCH STRATEGY: We searched the Cochrane Airways Group trial register, MEDLINE (January 1985 to January 2006), reference lists, and abstracts of medical conferences. SELECTION CRITERIA: Controlled trials (randomised and non-randomised) of self-management education in patients with COPD. Studies focusing mainly on pulmonary rehabilitation and studies without usual care as a control group were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study quality and extracted data. Investigators were contacted for additional information. MAIN RESULTS: The reviewers included 15 group comparisons drawn from 14 trials. They assessed a broad-spectrum of interventions and health outcomes with different follow-up times. Meta-analyses could often not appropriately be performed because of heterogeneity among studies. The studies showed a significant reduction in the probability of at least one hospital admission among patients receiving self-management education compared to those receiving usual care (OR 0.64; 95% CI (0.47 to 0.89)). This translates into a one year NNT ranging from 10 (6 to 35) for patients with a 51% risk of exacerbation, to an NNT of 24 (16 to 80) for patients with a 13% risk of exacerbation. On the disease specific SGRQ, differences reached statistical significance at the 5% level on the total score (WMD -2.58; 95% CI (-5.14 to -0.02)) and impact domain (WMD -2.83; 95% CI (-5.65 to -0.02)), but these difference did not reach the clinically relevant improvement of 4 points. A small but significant reduction was detected in dyspnoea measured with the BORG-scale (WMD -0.53; 95% CI (-0.96 to -0.10)). No significant effects were found either in number of exacerbations, emergency department visits, lung function, exercise capacity, and days lost from work. Inconclusive results were observed in doctor and nurse visits, on symptoms other than dyspnoea, the use of courses of oral corticosteroids and antibiotics, and the use of rescue medication. AUTHORS' CONCLUSIONS: It is likely that self-management education is associated with a reduction in hospital admissions with no indications for detrimental effects in other outcome parameters. This would in itself already be enough reason for recommending self-management education in COPD. However, because of heterogeneity in interventions, study populations, follow-up time, and outcome measures, data are still insufficient to formulate clear recommendations regarding the form and contents of self-management education programmes in COPD. There is an evident need for more large RCTs with a long-term follow-up, before more conclusions can be drawn.

Effectiveness of ultrasound screening for developmental dysplasia of the hip.

OBJECTIVE: To determine the effectiveness of ultrasound screening for developmental dysplasia of the hip (DDH) after the neonatal period. DESIGN: Prospective cohort study. SETTING: Child health care centres. PARTICIPANTS: Infants attending the child health care centres. INTERVENTIONS: The intervention group (n = 5170) was screened by ultrasound at 1, 2, and 3 months of age. The control group (n = 2066) was screened by routine physical examination as part of the programme for child health surveillance at the child health care centres (CHC screening). For evaluation of the screening, the children in both the intervention and control group received an ultrasound examination after 6 months of age to detect any abnormality that might have been missed by the screening. RESULTS: The sensitivity of the ultrasound screening was 88.5%, and the referral rate 7.6%. As a result of the ultrasound screening, 4.6% of the children were treated. The sensitivity of the CHC screening was 76.4%, with a referral rate of 19.2%. The treatment rate was 2.7%. Of the treated children in the ultrasound screening group, 67% were referred before the age of 13 weeks, whereas in the CHC screening group only 29% were referred before this age. CONCLUSIONS: This study shows that ultrasound screening detects more children with DDH than CHC screening and that more of them are detected at an earlier age. To accomplish this, even fewer children have to be referred. However, even general ultrasound screening seems not to eradicate late cases of DDH. The higher treatment rate in the population screened by ultrasound may be a result of overtreatment.

Natural course of tympanic membrane pathology related to otitis media and ventilation tubes between ages 8 and 18 years.

OBJECTIVE: To present the course of tympanic membrane pathology in childhood and young adulthood after otitis media (OM) in early life. STUDY DESIGN: Prospective follow-up study. SETTING: Community study of a birth cohort. PATIENTS: Three hundred fifty-eight subjects with a positive and negative history of OM (OM+ or OM-) or ventilation tube insertion (VT+ or VT-) derived from a birth cohort that had been followed-up from preschool to adult age. METHODS: Standardized otomicroscopic examination performed at ages 8 and 18 years. MAIN OUTCOME MEASURES: Tympanic membrane abnormalities (i.e., tympanosclerosis, atrophy, atelectasis and retraction pockets of the pars tensa, and retraction of the pars flaccida). RESULTS: At the age of 8 years, tympanic membrane pathology was highly prevalent in the both OM+ subcohorts (OM+VT+, 92% and OM+VT-, 46%), whereas in the OM- ears (11%), tympanic membrane abnormalities were rare. In the subsequent 10-year period, many tympanic membrane abnormalities disappeared spontaneously, although the prevalence of tympanosclerosis remained substantial in the OM+VT+ cohort. CONCLUSION: The natural course of most tympanic membrane pathology associated with OM in early life is favorable over time, suggesting an intrinsic repair capacity of the tympanic membrane. Tympanosclerosis, the most prevalent sequelae of OM and treatment with VT, however, shows little tendency of resolution.

Ventilation tubes in infants increase the risk of otorrhoea and antibiotic usage.

1) PROBLEM/OBJECTIVE: The effect of ventilation tubes on acute otitis related symptoms (otorrhoea, earache, and fever) and on antibiotic usage was investigated in children with persistent otitis media with effusion, as part of a multicenter, randomised, controlled clinical trial. 2) METHODOLOGY: One hundred-eighty-seven children were randomly placed into either a watchful waiting group (WW group) (n = 94) or a group treated with ventilation tubes (VT group) (n = 93). Both groups were followed for 12 months. Data were collected from parental reports and from medical files kept by the attending ENT-surgeons. 3) RESULTS: There were significant differences in the reported frequency of otorrhoea (but not of earache or fever) between both groups during follow-up, i.e. children in the VT group had more episodes of otorrhoea than the children in the WW group (p < 0.003). As a consequence, children in the VT group had been prescribed antibiotics more often. 4) CONCLUSIONS: Young children treated with ventilation tubes due to persistent otitis media with effusion have a higher risk of developing otorrhoea because of the tubes, and they have a higher risk of needing treatment with antibiotics.

The secular trends in male:female ratio at birth in postwar industrialized countries.

Finnish investigators [Vartiainen et al. Environmental Chemicals and Changes in Sex Ratio: Analysis Over 250 Years in Finland. Environ Health Perspect 107:813-815 (1999)] presented the sex ratio of all newborn babies from 1751 to 1997 in order to evaluate whether Finnish long-term data are compatible with the hypothesis that the decrease in the ratio of male to female births after World War I and World War II in industrial countries is caused by environmental factors. They found an increase in the proportion of males from 1751 to 1920, which was interrupted by peaks in male births during World War I and World War II and followed by a decrease thereafter, similar to the trends in many other countries. The turning point of male proportion, however, preceded the period of industrialization and introduction of pesticides and hormonal drugs. Thus, a causal association between these environmental exposures and this decrease is unlikely. In addition, none of the various family parameters (e.g., paternal age, maternal age, age difference in parents, birth order) could explain the historical time trends. Vartiainen et al. concluded that at present it is unknown how these historical trends could be mediated. The postwar secular decline of the male:female ratio at birth is not an isolated phenomenon and parallels the decline of perinatal morbidity and mortality, congenital anomalies, and various constitutional diseases. This parallelism indicates a common etiology and may be caused by reduction of conceptopathology, as a correlate to increasing socioeconomic development. An inverted dose response or the dose-response fallacy due to vanishing male conceptuses explains the low sex ratios before World War I and World War II in newborns from black parents and from the lowest socioeconomic classes.

The effectiveness of cervical screening: a population-based case-control study.

The cervical smear histories of 36 women with invasive cervical cancer were compared to those of 120 age-matched controls, drawn from local registrar's offices. Of the cases 47% were screened at least once, while for the controls this figure was 68%. The relative risk of getting invasive cervical cancer for women screened at least once compared to women who were never screened was 0.32. The most important confounding factor was age at first intercourse. Contrary to other studies however, it was found that women who were younger when having first intercourse were screened more often. After correcting the relative risk of screened vs unscreened for age at first intercourse, the relative risk became 0.22. When the length of the interval since the last smear was considered, the relative risk was 0.18 when the smear was made between 2 and 5 years earlier and 0.30 when this smear was made more than 5 years earlier. These results support the assumption that screening is effective in the prevention of invasive cancer of the uterine cervix. Even a screening interval of more than 5 years provides considerable protection.

Generalizability of trial results based on randomized versus nonrandomized allocation of OME infants to ventilation tubes or watchful waiting.

The objective was to study the generalizability of trial results by comparing randomized patients to eligible but nonrandomized patients who received the same management. Implementation of trial results is only justifiable when the results can be generalized to the total domain population. The design was a multicentre randomized controlled trial on the effect of early screening and treatment with ventilation tubes on infants with otitis media with effusion. Randomized (n = 187) and nonrandomized eligible patients (n = 133) were followed up. The study population comprised children who were detected by auditory screening at the age of 9-12 months and who were subsequently diagnosed with persistent bilateral otitis media with effusion for 4-6 months. A significant difference was found in the distribution of some prognostic factors: more randomized children had older siblings, did not attend day care and had mothers with a lower educational level than the nonrandomized children. These factors, however, did not modify the outcome. No differences were found in mean hearing levels between the randomized and nonrandomized children: in both the randomized and nonrandomized children ventilation tubes improved the hearing level, especially after 6 months. However, in the long term (12 months), the hearing levels were equal again. The results of the randomized and nonrandomized patients were comparable. The results of this trial appear to be generalizable to the total domain population. The procedure of following up both randomized and nonrandomized patients is recommended when there is concern about selective participation and reduced generalizability.

Occupational physical activity and the occurrence of spontaneous abortion.

The influence of occupational physical activity on early pregnancy failure was examined in a population of 24 cleaners, 36 kitchen staff and 110 clerical workers from 39 Dutch hospitals who were enrolled before becoming pregnant between August 1987 and January 1989. The occupational energy expenditure was defined by an intensity and a fatigue score, which were studied alone and in combination with working hours and working speed. The occupational biomechanic load was defined by a peak and a chronic pressure score. The intensity and the fatigue score of the work, whether or not in combination with working hours and working speed, were not related to the occurrence of spontaneous abortion. Work involving a high biomechanic load, in particular high peak pressure scores, showed an odds ratio (OR) for spontaneous abortion of 3.1 (95% confidence interval [CI]: 1.1-8.9). There were strong indications that work involving bending (OR = 3.2; 95% CI: 1.3-9.8) rather than lifting (OR = 1.1; 95% CI: 0.3-3.4) was the main cause.

Validity and reliability of a questionnaire on fecundability.

The validity of a short questionnaire on fertility problems was tested on a group of 151 moderately educated women who had participated in a prospective study on early pregnancy failure some years before. Part of this group was approached by a personal interview, another part by telephone interviews and a third part was sent a questionnaire by mail. Reliability was tested on another population of 89 women with at least one child. The questionnaire was presented to these women twice with an interval of 3-5 weeks. The validity study showed no systematic errors for either of the approaches. Random errors were fairly large except for the personal interviews. The reliability showed great stability for the telephone interviews as well as for the mailed questionnaire. It is concluded that the questionnaire performs reasonably well, but on some items the draft questionnaire should be rephrased. The choice of a specific approach to the study population depends on the research question.

Cervical cancer mortality in the Netherlands.

In this study cervical cancer mortality figures for the period 1936-1985 were evaluated. Trends in age-specific rates were analysed by separating the variations attributable to age at death, period of birth and period of death. Cervical cancer mortality has been decreasing since 1960 and this decline has become more rapid since about 1975. Organized screening, which began in 1976 could be responsible for the acceleration in the decline, but since the decline was already evident before screening was started, other factors must play a role. It seemed likely that a fall in incidence or an improvement in early diagnosis were responsible for the decline. Cohort analysis showed an increased risk for younger age groups but since the observations were derived from few five-year age-specific mortality rates no firm conclusions about future trends can be made.

Analysis and presentation of data on the natural course of otitis media with effusion in children.

Methods of analysing and presenting longitudinal data on health characteristics that have a fluctuating course are by no means standard. Several possibilities are discussed and tried out on longitudinal data on Otitis Media with Effusion (OME) in Dutch children. If the purpose of a study is descriptive, a graphical presentation based on an idea from Fiellau-Nikolajsen is preferred. For estimation purposes on the other hand, hazard functions are the most suitable. Further reduction of the data does not lead to a clear view into the complex nature of the course of a disease such as OME.

Excess seasonality of births among patients with schizophrenia and seasonal ovopathy.

In this study we examined whether the well-known winter excess of schizophrenic births exists among Dutch schizophrenia patients when statistical artifacts such as the age-incidence and age-prevalence effects are avoided and, if so, whether the seasonal preovulatory release of overripe ovum (SPrOO) hypothesis, that is, seasonally bound ovopathy, might be an explanation for this excess. We analyzed the month-of-birth distribution of 1,037 Dutch schizophrenia patients born between 1962 and 1966 and first admitted to a psychiatric hospital between 1978 and 1990 by the so-called window analysis to avoid the artifacts mentioned. The results show a winter excess of births among Dutch schizophrenia patients, even when statistical artifacts are avoided, and that the SPrOO hypothesis might be an explanation for this excess. Further research is needed to support the hypothesis that ovopathy, either seasonally bound or not, could be involved in the etiology of schizophrenia.

Male factor subfertility: possible causes and the impact of nutritional factors.

OBJECTIVE: To review possible causes for male factor subfertility with emphasis on nutritional factors such as zinc and folate. DESIGN: A literature search was performed on MEDLINE and via bibliographies of published works. RESULT(S): Many causes for male factor subfertility are described in the literature. Both environmental and genetic factors could play a role. However, the pathogenesis of male factor infertility is poorly understood, including the role of specific micronutrients such as zinc and folate. Both zinc and folate are involved in the synthesis of DNA and RNA. Despite the fact that zinc deficiency leads to several clinical symptoms such as decreased spermatogenesis and impaired male fertility, the exact pathophysiology has not been clarified. CONCLUSION(S): Because most causes of male factor subfertility are unknown, more research is needed. Because male factor subfertility due to nutritional deficiencies is in principle amenable to curative and/or preventive action by supplementation, emphasis should be put on studies on the effect of specific nutrients on male fertility.

The impact of the woman's age on the success of standard and donor in vitro fertilization.

OBJECTIVE: To study the effect of the age of the woman who provides the oocytes or who receives the embryos on results of IVF-ET. DESIGN: Historical cohort study. Multivariate regression analysis was used to study the age effect continuously and after adjustment for confounding. SETTING: Patients of the University of Southern California, Los Angeles, California. PATIENT(S): Couples who underwent standard (n = 277) or donor IVF-ET (n = 294) between January 1991 and July 1995. INTERVENTION(S): One cycle of standard or donor IVF-ET. MAIN OUTCOME MEASURE(S): Successive IVF outcomes from number of oocytes to ongoing pregnancy and several measures of pregnancy loss. RESULT(S): The number of oocytes decreased with aging of the oocyte provider. More women who received oocytes from donors aged 20 to 23 years had at least one good embryo transferred than women who received oocytes from older donors. The age of the woman who received the embryos had no effect on IVF outcomes. In women > 40 years who underwent standard IVF, the probability of pregnancy decreased. No such relationships were observed for donor IVF, but all the oocyte donors were younger. CONCLUSION(S): An age effect for ongoing pregnancy was only found in women > 40 years who underwent standard IVF independent of the lower number of oocytes and suggests decreasing oocyte quality.