1. The valuable contribution of observational studies to nephrology Kitty J. Jager¹, Vianda S. Stel¹, Christoph Wanner², Carmine Zoccali³ and Friedo W. Dekker 1,4 1 ERA–EDTA Registry, Dept. of Medical Informatics, Academic Medical Center, Amsterdam, The Netherlands 2 University of Würzburg, Division of Nephrology, University Clinic, Würzburg, Germany 3 CNR–IBIM Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Renal and Transplantation Unit, Ospedali Riuniti, 89125 Reggio Cal., Italy 4 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands Kidney International: Series on epidemiology

2. Study design In studies on the effects of therapy (or other interventions) the Randomized Controlled Trial (RCT) is an almost unbeatable standard in clinical research, as the randomization procedure helps to prevent selection bias by breaking the link between the clinicians therapy prescription and the patients prognosis RCTs Cohort studies Case-control studies Case reports & case series Potential to establish causality in studies on the effects of therapy Figure Contribution of different study designs to clinical research. The increase in evidence from the bottom to the top only applies to studies on the effect of therapy (or other interventions) As cross-sectional studies play a very limited role in studies on effects of therapy, this study design was not included in the figure

3. Limitations of RCTs RCTs are not possible –High cost –Ethics - e.g. dialysis vs conservative treatment RCTs may be inappropriate –Adverse effects RCTs may be inadequate –Selected populations e.g. NECOSAD - RCT HD vs PD RCTs may be unnecessary –Dramatic effects – e.g. insulin in Type 1 DM

4. Observational studies – where do they apply? Usually first step to generate and test hypotheses, but have less potential in making causal inferences Studies on etiology, diagnosis, prognosis and adverse effects

5. Case Report / Case Series Casadevall N, Nataf J, Viron B et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002;346:469-475. Example 1 – recombinant human erythropoietin (epoetin) and the development of pure red-cell aplasia (PRCA) In a series of 13 patients with chronic renal failure Casadevall et al. described a relationship between the use of recombinant human erythropoietin (epoetin) and the development of pure red-cell aplasia (PRCA). Their paper is an example of the discovery of a new and rare adverse event as a result of the exposure to a specific drug. After publication of this paper evidence about more cases became available from observational studies and eventually the likely cause of the problem was found. Study designStrengthsWeaknesses Case report/case seriesFirst form of publication for new diseases, rare adverse events or manifestations of disease Fast and inexpensive Hypothesis generating Very limited potential to make causal inferences, unless in dramatic cases Selection bias

6. Cross-sectional study Hallan SI, Coresh J, Astor BC et al. International comparison of the relationship of chronic kidney disease prevalence and end-stage renal disease risk. J Am Soc Nephrol 2006; 17: 2275–2284. Example 2 – comparing the prevalence of chronic kidney disease Hallan et al. used data from population based surveys, a type of cross-sectional study, when they sought to explain the difference in the incidence of ESRD between Norway and the US by comparing the prevalence of chronic kidney disease (CKD). Despite the much lower incidence of ESRD in Norway, the prevalence of CKD was similar in both countries. Study designStrengthsWeaknesses Cross-sectional studyCan assess prevalence and burden of disease Fast and inexpensive Hypothesis generating Very limited potential to make causal inferences, because time order of exposure and outcome cannot be determined Selection bias Survival bias

7. Case-control study Parikh CR, McCall D, Engelman C, Schrier RW. Congenital Renal Agenesis: Case-Control Analysis of Birth Characteristics. Am J Kidney Dis 2002;39:689-694 Example 3 – congenital renal agenesis Parikh et al. aimed to determine prenatal and perinatal factors associated with the development of renal agenesis. Cases were live birth infants with renal agenesis as reported in a state-wide birth registry; controls were a random sample of all births in that registry that were not reported to have renal agenesis. After adjustment for a number of factors, pre-existing maternal diabetes mellitus was associated with a higher risk of renal agenesis. The data also suggested a positive association with exposure to alcohol. Study designStrengthsWeaknesses Case-control studyEfficient study design Very suitable for studying rare outcomes and outcomes that take a long time to develop Can study multiple exposures Relatively inexpensive Hypothesis generating Some potential to make causal inferences Can study only one outcome at the time Choice of controls needs careful attention Selection bias Recall bias

8. Cohort study de Mutsert R, Snijder MB, van der Sman-de Beer F et al. Association between body mass index and mortality is similar in the hemodialysis population and the general population at high age and equal duration of follow-up. J Am Soc Nephrol 2007;18:967–974. Example 4 – Body Mass Index (BMI) and mortality De Mutsert et al. assessed BMI at the start of dialysis and recorded death during follow- up. They were able to show that in hemodialysis patients being underweight was associated with an increased risk of death, but any effect of obesity was not statistically significant. Study designStrengthsWeaknesses Cohort studyCan study multiple exposures, uncommon exposures and multiple outcomes Hypothesis generating Some potential to make causal inferences If done prospectively, more expensive If done prospectively, may take a long time to complete Selection bias

9. Conclusion Despite a number of objections the RCT remains the standard for studies on the effects of therapy The hierarchy of study designs only holds for studies on the effects of therapy In studies on etiology, diagnosis, prognosis or adverse effects observational studies are much more important than RCTs. In those cases any hierarchy of study designs is much less useful. Both observational studies and RCTs fulfill a complementary and valuable role in nephrology Clinicians should be aware of the strengths and weaknesses of each study design