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In evidence‐based medicine, clinical research questions may be addressed by different study designs. This article describes when randomized controlled trials (RCT) are needed and when observational studies are more suitable. According to the Centre for Evidence‐Based Medicine, study designs can be divided into analytic and non‐analytic (descriptive) study designs. Analytic studies aim to quantify the association of an intervention (eg, treatment) or a naturally occurring exposure with an outcome. They can be subdivided into experimental (ie, RCT) and observational studies. The RCT is the best study design to evaluate the intended effect of an intervention, because the randomization procedure breaks the link between the allocation of the intervention and patient prognosis. If the randomization of the intervention or exposure is not possible, one needs to depend on observational analytic studies, but these studies usually suffer from bias and confounding. If the study focuses on unintended effects of interventions (ie, effects of an intervention that are not intended or foreseen), observational analytic studies are the most suitable study designs, provided that there is no link between the allocation of the intervention and the unintended effect. Furthermore, non‐analytic studies (ie, descriptive studies) also rely on observational study designs. In summary, RCTs and observational study designs are inherently different, and depending on the study aim, they each have their own strengths and weaknesses., SUMMARY AT A GLANCE In evidence‐based medicine, clinical research questions may be addressed by different study designs. In this article, we explain that randomized controlled trials and observational study designs are inherently different, and depending on the study aim, they each have their own strengths and weaknesses.

Background Anemia-correction trials indicated higher mortality rates in chronic kidney disease patients assigned to higher hemoglobin targets. The safety of the high erythropoiesis-stimulating agent (ESA) doses that these patients received has therefore been questioned. However, no trial that directly compares treatment with different ESA doses has been published. We thus aimed to estimate the effect of high ESA dose on mortality in an observational cohort of dialysis patients. Methods The Netherlands Cooperative Study on the Adequacy of Dialysis is a Dutch cohort study of incident dialysis patients in which ESA dose, comorbidities, and laboratory parameters were collected every 6 months. Mortality in patients with a high ESA dose (above median 6000 units/week) was compared with that in patients with no or low ESA dose with Cox regression analyses. To handle time-dependent confounding, a sequential Cox approach was used conditional on baseline covariates, with inverse probability of censoring weights (IPCW) for dependent censoring. Analyses were repeated with a marginal structural model (MSM) with inverse probability of treatment weights and IPCW. Results Hazard ratio (HR) for high ESA dose was 1.20 (95%CI 0.83–1.73) with a sequential Cox and 1.54 (95%CI 1.08–2.18) with an MSM. Truncation of weights in the MSM did not affect estimates. To compare, conventional Cox analyses indicated a baseline adjusted HR of 1.66 (95%CI 1.20–2.31). Conclusion Patients treated with high ESA dose have a 1.2–1.5 increased risk of mortality. Our analyses support guidelines advising a conservative ESA dosing regimen, which carefully weighs the patients' benefits and risks. Copyright © 2015 John Wiley & Sons, Ltd.

Because maternal seropositivity for CMV is associated with substantial protection against congenital CMV infection, prevention measures have focused mainly on seronegative pregnant women for decades. However, population-wide insight in the contribution of nonprimary infection (reactivation and/or re-infection with a different strain) on the most common sequela, hearing loss, is missing. A population-based prediction model was developed to estimate the proportion of congenital CMV-related hearing loss resulting from nonprimary maternal infection. Incorporated was a meta-analysis of the risk of hearing loss, calculating pooled proportions of children with hearing loss after nonprimary and primary infection. Subsequently, the model was applied for worldwide present population seroprevalences (range 30-95%). It was estimated that, for all population seroprevalences, nonprimary maternal infections are responsible for the majority of congenital CMV infections. This proportion increased with seroprevalence, ranging from 57% (95%CI 24-85%) to 96% (95% CI 88-99%) for seroprevalences of 30% to 95%. Our meta-analysis (six reports) showed that the risk of hearing loss after nonprimary infection was 11% (28/253 children, 95% CI 7-15%) versus 13% (50/385 children, 95% CI 10-16%) after primary infection. Incorporating this risk into our model, we estimated that nonprimary infections also accounted for the majority of CMV-related hearing loss. This proportion ranged from 53% (95% CI 13-86%) to 95% (95% CI 62-99%) for seroprevalences of 30% to 95%. Our data underline the worldwide contribution of nonprimary infections in causing CMV-related hearing loss. These results imply that prevention research such as vaccine and hygiene studies should not only be directed at seronegative but also seropositive pregnant women. © 2013 John Wiley & Sons, Ltd.

Introduction: The causes of Permanent Childhood Hearing Impairment (PCHI) are often quoted as being hereditary in 50%, acquired in 25%, and unknown in 25% of cases. Interest in the causes of PCHI has grown recently due to increasing diagnostic possibilities. We investigated the evidence for the reported distribution of these causes. Methods: Population-based study and a systematic review. Inclusion criteria for population-based study: children born between 2003 and 2005, resident in The Netherlands at birth, known at an Audiology Center with PCHI at the age of 3-5 years. The causes of PCHI were determined prospectively by detection of congenital cytomegalovirus on dried blood spots and/or genetic diagnostic investigations in addition to reviewing data from medical records. A systematic review was carried out using three terms (hearing loss, infant, and etiology) and limited to articles published between January 1997 and July 2009. Main outcome measures were: the (weighted) proportions of the various causes of PCHI following diagnostic investigations. Results: In the study-population (n = 185) a hereditary cause was found in 38.9%, acquired cause in 29.7%, miscellaneous cause in 7.1%, and the cause remained unknown in 24.3%. The systematic review of the literature (n = 9 articles) resulted in a weighted mean of 30.4% hereditary, 19.2% acquired, and 48.3% unknown causes of PCHI. Discussion: The systematic review and the results of the population-based study provided little support for the generally accepted distribution of causes of PCHI.

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age-specific mortality rates for European patients on dialysis (n=274,221; follow-up=594,767 person-years), for European patients with a functioning kidney transplant (n=61,286; follow-up=345,024 person-years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmical mortality curve for patients on dialysis compared to both patients with a functioning kidney transplant and the general population (p

AIM: To provide growth and sexual maturation reference data for Moroccan children living in The Netherlands and to compare them with the reference data of children of Dutch origin. METHODS: Cross-sectional growth and demographic data were collected from 2880 children of Moroccan origin and 14,500 children of Dutch origin living in The Netherlands in the age range 0-20 y. Growth references for length, height, weight, weight-for-height, body mass index (BMI) and head circumference were constructed with the LMS method. Predictive variables for height and BMI were assessed by regression analyses. Reference curves for sexual maturation were estimated by a generalized additive model. RESULTS: Moroccan young adults were on average 9 cm shorter than their Dutch contemporaries. Mean final height was 174.7 cm for males and 161.3 cm for females. Height differences in comparison with Dutch children increase from 2 y onwards. Height SDS was predominantly associated with target height. Compared to Dutch children, maturation started 0.2 and 0.9 y later for girls and boys, respectively. Median age at menarche was 12.9 y, 3.6 mo earlier than in Dutch girls (p = 0.001). BMI of Moroccan children was above that of Dutch children, especially for girls. BMI SDS was associated with birthweight in the age group 0 - < or = 5 y. CONCLUSION: Moroccan children living in The Netherlands are substantially shorter than Dutch children. Girls have higher weight-for-height and BMI for age. Median age at menarche occurs earlier. Given these differences, separate growth charts for the Moroccan children are useful.

Summary objectives The importance of facial disfigurement in many diseases necessitates a reliable and valid measure of disfigurement severity for clinical studies. The hypothesis is that a universal concept of disfigurement exists and can be measured in a reliable way. The objectives of this study were to investigate if persons, in particular patients and physicians, can agree on facial disfigurement severity; and to determine the relative contribution of predefined clinical characteristics of patients with Graves’ ophthalmopathy (GO) to the overall rating of facial disfigurement severity. design A panel study was carried out in four different panels, each consisting of four members. patients We randomly selected 100 slide pairs of GO patients from four available study populations, involving mild, moderate and severe GO patients (mean age 49 years, 76% female) who were treated with either radiotherapy, sham-irradiation, prednisone or orbital decompression. measurements All panel members individually scored the disfigurement severity of 100 GO patients shown on standardized slides on a Visual Analog Scale. In total, 1600 ratings were collected. We calculated within- and between-panel agreement of disfigurement severity and identified determinants of disfigurement. results Agreement within a panel varied from 0·65 to 0·79 and was highest within the panel of ophthalmologists. Between-panel agreement was 0·67 and was highest between ophthalmologists and laypersons. Compared with the global average, patients overrated and endocrinologists underrated disfigurement severity. Female panellists rated the patients, on average, more disfigured than male panellists. Important determinants of disfigurement were eyelid retraction, severe eyelid swelling and proptosis. Their relative importance was consistent across panels and in contrast to current measures of GO severity. conclusion Facial disfigurement severity can be measured in a reliable way using panels of panellists. Except for some systematic differences between panellists, facial disfigurement does not seem to be in the eye of the beholder.

A high delivered Kt/Vurea is advocated in the DOQI guidelines on hemodialyis (HD) adequacy. However, the contribution of residual renal function to overall urea clearance is neglected. We investigated the relative contribution of residual renal Kt/Vurea and delivered Kt/Vurea to patient survival. Furthermore, we investigated whether other characteristics of HD treatment may be independently associated with survival. The NECOSAD study is a prospective multi-center study and includes ESRD patients older than 18 years who start dialysis as their first renal replacement therapy. We analyzed the longitudinal data on residual renal function and dialysis adequacy of those patients who were treated with HD 3 months after the start (n = 704). The mean age was 62 years. The mean renal Kt/Vurea at 3 months was 0.7/week (SD: 0.6) and the mean dialysis Kt/Vurea at 3 months was 2.7/week (SD: 0.8). The 2-year survival was 73.5%. Both a higher weekly renal Kt/Vurea and a higher delivered Kt/Vurea were significantly and independently associated with a better survival (P values

Summary OBJECTIVE The Graves’ ophthalmopathy quality of life questionnaire (GO-QOL) is the first instrument available to measure health-related quality of life (HRQL) of patients with Graves’ ophthalmopathy. The main objective of this study was to define a minimal clinically important difference (MCID) in score on the GO-QOL that can be considered an important improvement in HRQL by examining changes in GO-QOL scores in patients who subjectively report improvement from their treatment. A secondary objective was to test the longitudinal validity of the GO-QOL, using prespecified hypotheses about expected treatment effects.

Sufficient reference values for motor nerve conduction velocity (MNCV) in very preterm infants are not yet available. In the placebo infants within an L-thyroxine supplementation trial, born at less than 30 weeks' gestation, ulnar and posterior tibial MNCV measurements were performed shortly after birth. Repeated measurements were done at 2 weeks, at term, and at 6 months corrected age. Cross-sectional MNCV values obtained in 50 infants and longitudinal MNCV values obtained in 15 infants were analyzed in relation to postmenstrual age (PMA). Mean ulnar MNCV increased from 13 to 44 m/s and mean tibial MNCV from 11 to 37 m/s. Motor nerve conduction velocity was clearly related to PMA. Longitudinal MNCV values were consistent with cross-sectional MNCV values. Possible confounding factors did not have any significant effect on MNCV. In the ulnar nerve, extrauterine maturation during the first 2 weeks of life was delayed compared with intrauterine maturation.

Two-hundred infants of