This document discusses the importance of openness and quality in research. It covers principles like trial registration, ethics review, and transparent reporting of methods and results. Specifically, it emphasizes pre-specifying analysis plans, clearly reporting statistical methods and presenting uncertainties through confidence intervals rather than relying solely on p-values. Overall, it argues for following established guidelines to ensure research integrity and allow others to verify findings.

1. Öppenhet och kvalitet i forskningen

2. Jonas Ranstam Statistiker - Driftschef NKO (nat. komp. centr. rörelseorganens sjd.) ‏ - tidigare universitetslektor i medicinsk statistik och i epidemiologi, konsult/anställd statistiker i industrin - 200+ publikationer (bl.a. en serie om 10 metodartiklar i Acta Radiologica 2008)‏ Redaktionella uppdrag - Acta Orthopaedica, 1993 - - Statistical Methods in Medical Research, 2000 - 2005 - Osteoarthritis and Cartilage, 2008 -

3. Öppenhet och kvalitet i forskningen Plan 1. Kort bakgrund 2. Prövningsregistrering 3. Etikprövning 4. Resultatredovisning

4. 1. Kort bakgrund

6. Anecdotal evidence (Case reports)‏

7. Klinisk forskning Före 1948 Auktoritetsuppfattningar med oklar validitet och okänd osäkerhet beträffande urval och mätfel. - Prof A:s patienter har bättre resultat än Prof B:s - Små patientserier eller enstaka fall

8. Streptomycin in Tuberculosis Trials Committee. Streptomycin treatment of pulmonary tuberculosis. BMJ 1948;2:769-83. The Control Scheme Determination of whether a patient would be treated by streptomycin and bed-rest (S case) or by bed-rest alone (C case) was made by reference to a statistical series based on random sampling numbers drawn up for each sex at each centre by Professor Bradford Hill; the details of the series were unknown to any of the investigators or to the co-ordinator and were contained in a set of sealed envelopes, each bearing on the outside only the name of the hospital and a number.

9. Klinisk forskning Från 1948 Kvantitativ vetenskap med eliminering/reducering av bias och fastställning av statistisk precision - Randomisering och blindning (etikproblem)‏ - Stratifiering eller effektmodellering - Beräkning av statistisk precision (p-värde, statistisk styrka, konfidensintervall)‏

10. Anecdotal evidence (Case reports)‏ Cohort study of smoking and lung cancer (1954)‏ (Bradford Hill & Doll)‏ Case-control study of smoking and lung cancer (1950)‏ (Bradford Hill & Doll)‏ Randomised clinical trial of streptomycin and tubercolosis (1948)‏ (Bradford Hill, Daniels & D'Arcy Hart)‏

11. Anecdotal evidence (Case reports)‏ Evidence based medicine (The Cochrane collaboration 1993)‏ Cohort study of smoking and lung cancer (1954)‏ (Bradford Hill & Doll)‏ Case-control study of smoking and lung cancer (1950)‏ (Bradford Hill & Doll)‏ Randomised clinical trial of streptomycin and tubercolosis (1948)‏ (Bradford Hill, Daniels & D'Arcy Hart)‏

12. Prövningsregistrering (2005)‏ Etikprövningslag (2004)‏ EU-direktiv (2001)‏ CONSORT (1996)‏ ICH GCP (1996)‏ WHO CIOMS (1993)‏ Vancouverkonventionen (1978)‏ Helsingforsdeklarationen (1964)‏ Nürnbergkonventionen (1949)‏

13. 2. Prövningsregistrering

17. What if I didn't register my trial?‏ The ICMJE member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrollment. This policy applies to any clinical trial starting enrollment after July 1, 2005. For trials that began enrollment prior to this date, the ICMJE member journals will require registration by September 13, 2005, before considering the trial for publication. We speak only for ourselves, but we encourage editors of other biomedical journals to adopt similar policies .

18. ICMJE member journals Journal of the American Medical Association The New England Journal of Medicine The New Zealand Medical Journal Norwegian Medical Journal Canadian Medical Association Journal The Lancet Annals of Internal Medicine Croatian Medical Journal Dutch Journal of Medicine Journal of the Danish Medical Association The Medical Journal of Australia

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21. Medicinska tidskrifter vid Lunds universitets bibliotek

23. 3. Etikprövning

24. The Helsinki Declaration: BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information... General statistical issues - Sample size calculation - Randomization procedure - Multiplicity issues - Etc.

25. ICMJE II.F. Protection of Human Subjects and Animals in Research When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).

26. WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for Medical Research Involving Human Subjects 27. ... Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.

27. International Ethical Guidelines for Biomedical Research Involving Human Subjects Prepared by the Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO)‏ Commentary on Guideline 2 ... Unless there are persuasive reasons to do otherwise, editors should refuse to publish the results of research conducted unethically, and retract any articles that are subsequently found to contain falsified or fabricated data or to have been based on unethical research.

28. No ethics review was performed because - the tried drug was already on the market - side effects are minimal - we did not consider the trial ethically problematic - ... was not an EU member when the trial started - etc.

30. 4. Resultatredovisning

31. The responsibilities of a statistical reviewer “ To make sure that the authors spell out for the reader the limitations imposed upon the conclusions by the design of the study, the collection of data, and the analyses performed.” Shor S. The responsibilities of a statistical reviewer. Chest 1972;61:486-487.

33. Statistical Methods “ Describe statistical methods with enough detail to enable a knowledgeable reader with access to the original data to verify the reported results.”

34. Statistical Methods “ Describe statistical methods with enough detail to enable a knowledgeable reader with access to the original data to verify the reported results.” - This means detailed information on methods, inclusion/exclusion criteria, adjustment factors, transformation of variable, parametrisation, etc.

35. Results “ When possible, quantify findings and present them with appropriate indicators of measurement error or uncertainty (such as confidence intervals).”

36. Results “ When possible, quantify findings and present them with appropriate indicators of measurement error or uncertainty (such as confidence intervals).” - P-values and confidence intervals are used to quantify the influence of sampling uncertainty and measurement errors. - P-values (or *, **, *** and ns) do not describe clinical importance.

37. Results “ Avoid relying solely on statistical hypothesis testing, such as the use of P values, which fails to convey important information about effect size.”

38. Results “ Avoid relying solely on statistical hypothesis testing, such as the use of P values, which fails to convey important information about effect size.” - Absence of evidence is not evidence of absence - Confidence intervals allow interpretation of results in terms of clinical significance

39. 0 Effect Clinically significant effect Statistically and clinically significant effect Statistically, but not necessarily clinically, significant effect Inconclusive Neither statistically nor clinically significant effect Statistically significant reversed effect p < 0.05 p < 0.05 n.s. n.s. p < 0.05 P-value Conclusion from confidence intervals P-values vs. confidence intervals

40. Results “ Where scientifically appropriate, analyses of the data by variables such as age and sex should be included.”

41. Results “ Where scientifically appropriate, analyses of the data by variables such as age and sex should be included.” - Adjustment for confounding factors (do not use automatic stepwise regression)‏ - Presentation of crude and adjusted estimates

42. Clinical trials “ For reports of randomized controlled trials authors should refer to the CONSORT statement.”

46. Studieprotokoll (och SAP)‏ Många tidskrifter kräver in studieprotokoll och jämför informationen i detta med innehållet i manuskriptet - patientantal - primary endpoint - multiplicitetsfrågor - studiepopulation (ITT/PP)‏ - imputering - interimsanalyser - etc.

47. Clinical trials International guidelines ICH Topic E9 - Statistical Principles for Clinical Trials EMEA Points to consider - baseline covariates - missing data - multiplicity issues - etc. These guidelines can all be found on the internet.

48. Tack för uppmärksamheten!