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Öppenhet och kvalitet i forskningen

Lund 30.09.2008

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Page 1: Lund 30.09.2008

Öppenhet och kvalitet i forskningen

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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 -

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Öppenhet och kvalitet i forskningen

Plan

1. Kort bakgrund

2. Prövningsregistrering

3. Etikprövning

4. Resultatredovisning

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1. Kort bakgrund

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Anecdotal evidence

(Case reports)

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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

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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.

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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)

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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)

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Anecdotal evidence

(Case reports)

Evidence basedmedicine

(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)

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Prövningsregistrering (2005)

Etikprövningslag (2004)

EU-direktiv (2001)

CONSORT (1996)

ICH GCP (1996)

WHO CIOMS (1993)

Vancouverkonventionen (1978)

Helsingforsdeklarationen (1964)

Nürnbergkonventionen (1949)

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2. Prövningsregistrering

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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.

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ICMJE member journals

Journal of the American Medical AssociationThe New England Journal of MedicineThe New Zealand Medical JournalNorwegian Medical JournalCanadian Medical Association JournalThe LancetAnnals of Internal MedicineCroatian Medical JournalDutch Journal of MedicineJournal of the Danish Medical AssociationThe Medical Journal of Australia

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ACADEMIC MEDICINE (formerly Journal of Medical Education)

ACTA CHIRURGICA HELLENICA ACTA GASTROENTEROLOGICA BOLIVIANA

ACTA HAEMATOLOGICA

ACTA MEDICA

ACTA MEDICA COLOMBIANA ACTA MEDICA HELLENICA - see "HELLINIKI IATRIKI"

ACTA MEDICA SCANDINAVICA - see "JOURNAL OF INTERNAL MEDICINE"

ACTA ORTHOPAEDICA SCANDINAVICA

ACTA PAEDIATRICA JAPONICA

ACTA PAEDIATRICA SCANDINAVICA

ACTA PHARMACOLOGICA SINICA

ACTIVOX ACUPUNCTURE IN MEDICINE

ACUTE CARE

ADOLESCENT AND PEDIATRIC GYNECOLOGY

AIDS: AN INTERNATIONAL BIMONTHLY JOURNAL

AJR: AMERICAN JOURNAL OF ROENTGENOLOGY

AMERICAN JOURNAL OF ALZHEIMER'S DISEASE AND OTHER DEMENTIAS (list date 6/8/06)

AMERICAN JOURNAL OF CLINICAL RESEARCH

AMERICAN JOURNAL OF DISEASES OF CHILDREN

AMERICAN JOURNAL OF HOSPITAL PHARMACY

AMERICAN JOURNAL OF NONINVASIVE CARDIOLOGY

AMERICAN JOURNAL OF OPTOMETRY AND PHYSIOLOGICAL OPTICS

AMERICAN MEDICAL WRITERS ASSOCIATION

AMERICAN REVIEW OF RESPIRATORY DISEASE ANAESTHESIA

ANESTHESIA AND ANALGESIA

ACTA ANATOMICA

ACTA OTORRINOLARINGOLÓGICA ESPAÑOLA (list date 3/7/07)

AMERICAN FAMILY PHYSICIAN

AMERICAN HEART JOURNAL

AMERICAN JOURNAL OF CARDIOVASCULAR DRUGS (list date 4/8/08) AMERICAN JOURNAL OF CLINICAL DERMATOLOGY (list date 4/8/08)

AMERICAN JOURNAL OF EPIDEMIOLOGY

AMERICAN JOURNAL OF NEPHROLOGY

AMERICAN JOURNAL OF OBSTETRICS & GYNECOLOGY

AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY

ANAESTHESIA AND INTENSIVE CARE

ANALES DE PEDIATRÍA

ANALYTISCHE PSYCHOLOGIE

682

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Area # journalsAllergy and immunology 40Anesthesiology and intensive care 34Cardiovascular and respiratory system 156Complementary and alternative medicine 20Dentistry 91Dermatology 47Endocrinology and diabetes 34Gastroenterology 61Genitourinary system and urology 38Geriatrics 44Gynecology and obstetrics 113Hematology 21Human anatomy 13Internal medicine 644Medical technology and radiology 88Medicine (General) 629Musculoskeletal system, orthopedics and rheumatology 69Neurosciences 144Nursing 135Oncology 92Ophthalmology 48Otorhinolaryngology 36Pathology 92Pediatrics 151Pharmacy and materia medica 71Physical therapy (Physiotherapy) and occupational therapy 54Physiology 292Psychiatry 112Public health and social medicine 346Surgery 244Therapeutics. Rehabilitation. Pharmacology 214

In total 4173

Medicinska tidskrifter vid Lunds universitets bibliotek

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3. Etikprövning

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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.

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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).

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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.

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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.

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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.

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4. Resultatredovisning

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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.

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Statistical Methods

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

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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.

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Results

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

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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 toquantify the influence of sampling uncertainty and measurement errors.

- P-values (or *, **, *** and ns) do not describe clinical importance.

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Results

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

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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 resultsin terms of clinical significance

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0Effect

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

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Results

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

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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

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Clinical trials

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

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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.

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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.

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Tack för uppmärksamheten!