Gdansk bio-statistic and epidemiology course

Francesco Locatelli1,, Boleslaw Rutkowski2, Simeone Andrulli1, Giuseppe Enia3, Ryszard Gellert4, Reinhard Kramar5, Daniele Marcelli6, Carmine Zoccali3, Andrzej Wiecek7 and Eberhard Ritz8

1 Department of Nephrology, A. Manzoni Hospital, Lecco, Italy, 2 Department of Nephrology, Medical University, Gdansk, Poland, 3 Division of Nephrology, Centre of Clinical Physiology, Cardiology Unit of Morelli Hospital, Reggio Calabria, Italy, 4 Chair and Department of Medicine and Nephrology, Warsaw Medical University, Warsaw, Poland, 5 Third Department of Medicine, General Hospital, Barmherzige Schwestern vom Hl, Kreuz, Wels, Austria, 6 Fresenius Medical Care, Bad Homburg, Germany, 7 Department of Nephrology, Endocrinology and Metabolic Diseases, Silesian University Medical School, Katowice, Poland; on behalf of ERA-EDTA Action Nephrology Eastern Europe and 8 Department of Nephrology, University of Heidelberg, Heidelberg, Germany; on behalf of Joint Action Nephrology Eastern Europe

On 10–11 November, 2000, a bio-statistic and epidemiology course took place in Gdansk, Poland. The initiative, organized by Prof. Francesco Locatelli and Prof. Boleslaw Rutkowski, was promoted by the Joint Action Nephrology in Eastern Europe, chaired by Prof. Eberhard Ritz, and supported by the European Renal Association, and it was a part of the educational programme aimed at supporting the growing know-how in nephrological care and renal replacement therapy (RRT) in the Eastern European Countries.

Profound political and social changes have taken place in Eastern Europe in the last decade, and the countries of the former Soviet bloc are undergoing rapid economic development. The issue of how to best provide RRT, both from the clinical and socio-economical points of view, has become a major issue in such nations.

Evidence-based medicine, that is ‘the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients’ (Sackett DL), not only represents an indispensable tool for improving the state of art in clinical medicine and the patient outcome, but it is also the best way to rationally and ethically plan the nephrology Medicare, which is an increasing demand world-wide.

This is the reason why the Joint Action committee chose a bio-statistic and epidemiology course as a cornerstone in nephrological training. Twenty-five nephrologists from Eastern Europe participated to the course. It comprised both theoretical and practical lessons, in which the basic topics in bio-statistics and epidemiology were covered starting from relevant nephrological issues and exemplifying each concept by referring to the nephrological literature, in order to use a more familiar background for the participants and facilitate their comprehension of subjects which, traditionally, are not among the preferred ones by clinicians. Therefore, the course was held by senior nephrologists who had distinguished themselves not only on the basis of their statistical-methodological skills, but, above all, for their contribution in the different fields of clinical nephrology research. Moreover, the practical lessons were performed with the aid of computer exercises, using SPSS 10 Statistical Software for Windows, thus permitting the participants to apply the concepts taught into practical settings, as it is ordinarily made in the clinical research practice. In the organizers’ opinion, this has been a good exercise not only to critically evaluate medical literature, but also to promote original clinical research in the Eastern European countries.

The course started from the basics in bio-statistic: the measures of location and the measures of variation, under the tutoring of Drs G. Enia and S. Andrulli, respectively. In these basic lessons, the importance of proper initial assessment of the data as the first step in statistical analysis was emphasized. When you have obtained a set of data from any planned experiment, you have first to look at where the data are located, hence, the indices of location (mean, median, mode of the data distribution), and how much are they dispersed, hence, the indices of dispersion (range, variance, standard deviation, coefficient of variation). Moreover, it is very useful to represent the data graphically (e.g. histograms for quantitative data, bar charts for qualitative data). From this inspection of the basic data, it is possible to obtain information on the shape of the distribution (normal versus non-normal, skewness, and curtosis) and the presence of outliers. This has very practical implications. When outliers are present, one should always verify whether the data were correctly measured or inserted into the database, particularly if such data look ‘strange’. For example, serum potassium levels of 14.5 mEq/l are very likely the result of a mistake, perhaps of some operator who had reported 14.5 instead of 4.5 mEq/l. This may sound trivial, but one should not take it for granted that such a preliminary data check is ordinarily made. Furthermore, from indices of location and dispersion, one can have preliminary information as regards the data distribution, before using complex statistical tests. In fact, it was explained that the basic characteristics of normal, or bell-shaped, distributions is that 95% of the data are comprised in an interval the boundaries of which are given by the mean value±1.96xstandard deviation. Therefore, if a given data distribution, say of proteinuria values, had a mean value of 3 g/24 h and a standard deviation of 5, it would be clearly not normally distributed, and, without entering further details, this is quite relevant in order to choose the correct statistical tests for the analysis of data. In conclusion, a proper preliminary data inspection, with calculation of the measures of location and dispersion, is the basis for avoiding a lot of subsequent mistakes, of which many examples exist in medical literature.

The subsequent topic of the course was the survival analysis, under the tutoring of Dr D. Marcelli. This is probably the most important and frequent statistical analysis the clinicians have to deal with in their professional training. Survival analysis is focused on the time to event, such as death or dialysis, to occur from some fixed starting point, such as diagnosis or start of treatment. It gives information to estimate the probability of individuals surviving for a given time period, such as 1 year, without the event. With two or more groups, it permits comparison of their survival experience. During the lesson, the main characteristics of survival analysis were explained: the length of the follow-up differs among patients and we almost never observe the event of interest in all subjects, either because they had withdrawn from the study (lost to follow-up) or because at the end of the study they have not yet had the event. Such patients are indicated as censors, meaning that the period of observation was cut off before the event of interest occurred. The method of survival analysis makes use of the information coming from these subjects up to the time when they are censored, as well as of the information coming from the patients who had the event. During the practical session, it was shown how survival is represented by the statistical software as life tables and survival (or Kaplan–Meier) curves, and it was shown how to determine the survival rates at different time periods. Finally, the comparison between survival functions was discussed.

In the subsequent sessions of the course, the different study designs were illustrated, starting from the assumption that it is of paramount importance how the data are collected. In fact, in the setting of bio-statistics and epidemiology, the analysis of data is only a part of a thorough process starting with the choice of the best study design fitting with the hypothesis addressed in the study, the disease under investigation, the practical possibilities in which the researchers operate.

Prof. C. Zoccali introduced cohort and case-control studies. These study designs belong to the more general issue of observational studies, that are characterized by the fact that the variables of interest are not manipulated by researchers, and outcomes are simply observed in order to find out associations with risk factors. In cohort studies, patients are divided into cohorts according to the presence or absence of the putative risk factors, and the incidence of the events is prospectively recorded. The association between risk factors and events is quantified by the relative risk, which is the ratio of the incidence of events in exposed people over the incidence in non-exposed people. In case-control studies, patients are divided into groups according to the presence or absence of the event of interest, and the previous exposure to the putative risk factors is searched for in the patients’ history. The advantages and limitations of these study designs were explained and exemplified (focusing on biases, confounding factors, contamination, co-intervention, cohort effects, and ecologic fallacy).

Dr S. Andrulli introduced the clinical trials, defining them as any forms of planned experiments, related to patients, aimed at improving the treatment of other patients in future, with a well-characterized disease. It was explained that clinical trials are interventional studies in clinical research, and are characterized by the patients’ random assignment to different treatments (e.g. different dialysis doses or different dialysis membranes): patient outcomes are compared among the different treatment groups, while other potential confounding factors are controlled. The main characteristics of clinical trials, their advantages and limitations were discussed referring to the recently published randomized controlled clinical trials of: corticosteroids versus conservative therapy in IgA nephropathy with proteinuria [1]; the role of dietary protein restriction in slowing down the progression of chronic renal insufficiency [2]; and the use of the conductivity kinetic model in haemodiafiltration to improve the treatment tolerance [3].

Prof. F. Locatelli concluded the sessions dedicated to the study design with the presentations about meta-analyses, focusing on the lights and shades of this new technique of synthesising clinical studies. Referring to the role of dietary protein restriction in the progression of chronic renal insufficiency, the characteristics and limitations of meta-analyses were illustrated using an example, i.e. the papers by Pedrini [4] and by Kasiske [5].

The final sessions of the course were dedicated to renal Registries, focusing on their importance as sources of very large sets of data for observational studies, as they provide information collected from all of the patients belonging to a certain geographic area, thus concerning a whole population, not just a sample of it. Prof. R. Gellert illustrated the new ERA-EDTA Registry, referring also to the future organization and programme, evaluating the following topics: relevance, advantages and limitations of Registries; what we have learnt from Registry management; incidence and prevalence rates; comparison among Registries; co-morbidity indexes. Prof. R. Kramar exemplified, referring to the experience in Austria, how information technology can provide a valuable support to collect the data for renal Registries.

Prof. F. Locatelli illustrated the International Federation of Renal Registries, which is an international group founded by the chairmen of national and regional renal registries in 1997, whose aims are: to bring together investigators in renal epidemiology, to improve dialogue between the renal Registries for the standardization of renal databases, to improve common terminology and methodology for the analysis of clinical data, and to promote international collaborative studies. In his presentation, Prof. F. Locatelli also illustrated the essential features of the DOPPS Study (Dialysis Outcome Practice Patterns Study): an observational prospective multicentre study (309 centres, 10 000 patients enrolled), which is currently ongoing. Data are collected from seven countries (France, Germany, Italy, Spain, UK, USA, and Japan), from a nationally representative sample of dialysis facilities in each country and a random sample of haemodialysis patients within each participating centre. The aim is to study the effect of practice pattern variability on dialysis outcomes, in order to identify relevant, potentially causal, associations. It was stressed that the DOPPS Study is unique in the magnitude of the information prospectively and uniformly collected from a large sample of dialysis patients, representative of different countries and different continents (international and intercontinental study), which is nearly impossible for a renal Registry to achieve. The major findings of the DOPPS Study concerning dialysis dose and patient outcome were summarized.

Prof. B. Rutkowski concluded the course by illustrating the epidemiologic picture of RRT in Central and Eastern Europe from the national Registries [6]. It was a very interesting and stimulating presentation, as Registries in Central and Eastern Europe have been instituted in the recent past years, and are providing precious information on the evolving situation of RRT in these countries. For the participants, this was an occasion to take awareness of the growing dimensions of the RRT programme in their respective countries and also to insert it into the context of the neighbouring countries [7].

In conclusion, the bio-statistics and epidemiology course was a great success both for the organizers and the participants. Given its theoretical–practical formulation, oriented to nephrological issues, it was a unique opportunity, not only providing education in statistical methodological issues, but also providing a forum for an open debate on key topics in epidemiological and clinical research. The Joint Action Nephrology Eastern Europe and the European Renal Association strongly perceived that the collaboration and continuous exchange of information between nephrologists from Western and Eastern Europe is necessary condition for further improvement in nephrological care and research in the whole Continent. Therefore, they wish such series of education initiatives are continued in future, and thank all of the participants in the course and everyone who contributed to the success of this important initiative.

Notes

Correspondence and offprint requests to: Prof. Dr Francesco Locatelli, Department of Nephrology and Dialysis, Ospedale A. Manzoni, Via Dell'Eremo 9/11, I-23900 Lecco, Italy. Back

Further reading

  1. Pozzi C, Bolasco PG, Fogazzi GB et al. Corticosteroids in IgA nephropathy: a randomised controlled trail. Lancet 1999; 353: 883–887[ISI][Medline]
  2. Klahr S, Levey AS, Beck GJ et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994; 330: 877–884[Abstract/Free Full Text]
  3. Locatelli F, Andrulli S, Di Filippo S et al. Effect of on-line conductivity plasma ultrafiltrate kinetic modeling on cardiovascular stability of hemodialysis patients. Kidney Int 1998; 53: 1052–1060[ISI][Medline]
  4. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann Intern Med 1996; 124: 627–632[Abstract/Free Full Text]
  5. Kasiske BL, Lakatua JD, Ma JZ, Louis TA. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am J Kidney Dis 1998; 31: 954–961[ISI][Medline]
  6. Rutkowski B et al. Changing pattern of end-stage renal disease in central and eastern Europe. Nephrol Dial Transplant 2000; 15: 156–160[Abstract/Free Full Text]
  7. Rutkowski B, Ciocalteu A, Djukanovic L et al. Evolution of renal replacement therapy in central and eastern Europe 7 years after political and economical liberation. Nephrol Dial Transplant 1998; 13: 860–884[Abstract]