Thomas D. Szucs MD MBA MPH

Einführung in die Gesundheits- und
Krankheitsforschung
Thomas D. Szucs MD MBA MPH
forschungsmethodologie 1
Lernziele
• Am Ende des Kurses soll der Student
– Verstehen, welchen Stellenwert Krankheit und
Gesundheit haben
– Die wichtigsten Methoden der Gesundheits- und
Krankheitsforschung kennen
– Verstehen, wie konkrete Fragestellungen eigenständig
formuliert und entsprechende empirische Projekte
geplant werden
– Elementare quantitative und qualitative Verfahren der
Evaluationsforschung verstehen
– Forschungsergebnisse der Gesundheits- und
Krankheitsforschung grob interpretieren können
forschungsmethodologie 2
Page 1
Lernmethoden
•
•
•
•
•
Frontalunterricht (Magistralvorlesung)
Gruppendiskussionen
Miniprojekte in Kleingruppen
Übungen am PC
Lernkontrollen (Quiz und schriftliche Prüfung)
forschungsmethodologie 3
Die Herausforderungen des
Gesundheits (Krankheits-)wesens
forschungsmethodologie 4
Page 2
Atherothrombosis* is the Leading Cause
of Death Worldwide†1
Atherothrombosis*
52%
Cancer
24%
Infectious Disease
19%
Pulmonary disease
14%
12%
Violent death
AIDS
5%
0
10
20
30
40
50
60
Mortality (%)
*Cardiovascular disease, ischemic heart disease and cerebrovascular disease
†Worldwide defined as Member States by WHO Region (African, Americas, Eastern
Mediterranean, European, South-East Asia and Western Pacific).
1. World Health Organization. The World Health Report 2001. Geneva: WHO; 2001.
forschungsmethodologie 5
Lifetime Probability of Developing Cancer,
by Site, Men, US, 1998-2000
Site
Risk
All sites
1 in 2
Prostate
1 in 6
Lung & bronchus
1 in 13
Colon & rectum
1 in 17
Urinary bladder
1 in 29
Non-Hodgkin lymphoma
1 in 48
Melanoma
1 in 55
Leukemia
1 in 70
Oral cavity
1 in 72
Kidney
1 in 69
Stomach
1 in 81
Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 5.1 Statistical Research forschungsmethodologie
and Applications
6
Branch, NCI, 2003. http://srab.cancer.gov/devcan
Page 3
Todesfälle durch Tabak in USA im
Vergleich (1990)
Ursache
Tabak
Falsche Ernährung
Alkohol
Infektionen
Vergiftungen
Schusswaffen
Riskantes Sexualverhalten
Motorsportunfälle
Harte Drogen
Gesamt
# Todesfälle
% aller Todesfälle
400‘000
300’000
100‘000
90‘000
65‘000
35‘000
30‘000
25‘000
20‘000
1‘065‘000
Bartecchi CE et al. NEJM 1994; 330:13
19
14
5
4
3
2
1
1
<1
49
forschungsmethodologie 7
No EffectiveTreatment for Major
Diseases
forschungsmethodologie 8
Page 4
Change in the US Death Rates* by Cause,
1950 & 2001
Rate Per 100,000
600
586.8
1950
500
2001
400
300
245.8
200
193.9
180.7
100
57.5
48.1
194.4
21.8
0
Heart
Diseases
Cerebrovascular
Diseases
Pneumonia/
Influenza
* Age-adjusted to 2000 US standard population.
Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.
2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3.
http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf
Cancer
forschungsmethodologie 9
Atherothrombosis Will Remain the Leading
Cause of Disease Burden
The ten leading causes of disease burden in developed countries 1990–2020
1990 disease or injury1
Rank order
2020 disease or injury2
Ischemic heart disease
1
Ischemic heart disease
Cerebrovascular disease
2
Cerebrovascular disease
Road traffic accidents
3
Trachea bronchus and lung cancers
4
Self-inflicted injuries
5
Unipolar major depression
Trachea bronchus & lung
cancers
Road traffic accidents
Conditions arising during perinatal period
6
Alcohol use
Lower respiratory infections
7
Osteoarthritis
Congenital anomalies
8
Colon and rectal cancers
9
Stomach cancer
10
Dementia and other CNS disorders
Chronic obstructive pulmonary
disease
Self-inflicted Injuries
Note: Disease burden is measured in disability-adjusted life years (DALYs), a measure that combines the impact on health of years lost due to premature death and
years lived with a disability. One DALY is equivalent to one lost year of healthy life
1. Murray and Lopez. Global Burden of Disease Study. 1996
2. Murray and Lopez. Global Burden of Disease Study. 1997
forschungsmethodologie 10
Page 5
forschungsmethodologie 11
Flu vaccine production in eggs
forschungsmethodologie 12
Page 6
Choices in health care...
forschungsmethodologie 13
„Medicalisation“
forschungsmethodologie 14
Page 7
Wie alles geschah…
forschungsmethodologie 15
Sir James Lind (1716-1794)
To introduce any new article of food
among seamen, let it be ever so much for
their good, requires both examples and
the authority of a Commander.
James Cook
forschungsmethodologie 16
Page 8
A historical example: Scurvy
1601 Captian James Lancaster: 3 teaspoons
lemon juice per day
1747 James Lind: first RCT on HMS Salisbury
1795 British Navy order: all ships must provide citrus
fruits
1865 British Board of Trade: proper diets on all
merchant marine vessels
Total time elapsed until universal
British prevention policy: 264 years!
forschungsmethodologie 17
A Treatise of the Scurvy 1753
forschungsmethodologie 18
Page 9
Florence Nightingale (1820-1910)
“I am fine to sum up with an urgent
appeal for adopting this or some uniform
system of publishing the statistical
records of hospitals.
If they would be obtained, they would
show subscribers how their money was
being spent, what amount was really
being done with it, or whether the money
was doing more mischief than good.”
Florence Nightingale (1863)
forschungsmethodologie 19
forschungsmethodologie 20
Page 10
William Farr (1807-1883)
– Responsible for medical
statistics
– Began practice of mortality
surveillance
– Compared mortality rates of
married and single persons,
different occupations
– Examined role of exposures
(e.g., imprisonment) on
mortality
» Identified population at risk
» Chose comparison group
» Proposed possible causal
factors
» Identified possible
confounders
forschungsmethodologie
21
John Snow (1813-1858)
– “Father of Epidemiology”
– Noticed that death rates from
cholera high in a particular
area of London
– Charted the frequency and
distribution of cholera
» Death rates per 100,000
population according to
water company supplying the
sub district
Death rates per 10,000 houses
according to water company
supplying the house
– Combined the three
components in the definition
of epidemiology
» Distribution, determinants
and frequency
forschungsmethodologie 22
Page 11
Choleratote in Londoner Bezirke, welche
vom 8.7. bis 26.8.1854 durch 2 Wasserwerke versorgt wurden
Wasserwerk
Bevölkerung
1851
# Tote
Mortalitätsrate pro
1000
Personen
Southwark
167 654
844
5.0
Lambeth
19 133
18
0.9
Snow, 1855
forschungsmethodologie 23
Ignaz Semmelweis (1818-1865)
forschungsmethodologie 24
Page 12
Ignaz Semmelweis (1818-1865)
• In the 1840s, puerperal or
childbirth fever, a bacterial
infection of the female genital tract
after childbirth, was taking the
lives of up to 30% of women who
gave birth in hospitals.
• Women who gave birth at home
remained relatively unaffected.
• Semmelweis observed that women
examined by student doctors who
had not washed their hands after
leaving the autopsy room had very
high death rates.
• When a colleague who had
received a scalpel cut died of
infection, Semmelweis concluded
that puerperal fever was septic and
contagious.
• He ordered students to wash their
hands with chlorinated lime before
examining patients; as a result, the
maternal death rate was reduced
from 12% to 1% in 2 years.
forschungsmethodologie 25
Sir Richard Doll &
Sir Austin Bradford Hill
forschungsmethodologie 26
Page 13
1958 - Doll and Hill apply case-control
study design to establish smoking as
cause of lung cancer
forschungsmethodologie 27
forschungsmethodologie 28
Page 14
The first randomised drug trial
forschungsmethodologie 29
forschungsmethodologie 30
Page 15
The Streptomycin Study in Britain
forschungsmethodologie 31
World Health Organisation
• The World Health Organization is the
United Nations specialized agency for
health.
• It was established on 7 April 1948.
• WHO's objective, as set out in its
Constitution, is the attainment by all
peoples of the highest possible level of
health.
• Health is defined in WHO's Constitution as
a state of complete physical, mental and
social well-being and not merely the
absence of disease or infirmity.
• WHO is governed by 192 Member States
through the World Health Assembly.
• The Health Assembly is composed of
representatives from WHO's Member
States.
forschungsmethodologie
Page 16
32
The largest vaccine trial ever
"A calculated risk": the Salk
polio vaccine field trials of 1954
forschungsmethodologie 33
1948, a small town in Massachussetts: Framingham cohort study begun to study
coronary artery disease
forschungsmethodologie 34
Page 17
The Framingham Study
•
•
•
•
•
•
•
For 50 years, the Framingham Heart Study and the residents of Framingham, Massachusetts,
have been synonymous with the remarkable advances made in the prevention of heart disease in
the United States and throughout the world.
Fifty years of data collected from residents of Framingham have produced over 1,000 scientific
papers, identified major risk factors associated with heart disease, stroke and other diseases,
paved the way for researchers to undertake singular clinical trials based on Framingham findings,
created a revolution in preventive medicine, and forever changed the way the medical community
and general public view the genesis of disease.
The study is one of the most important epidemiological studies While its contributions in the area
of heart research are legion, researchers also are utilizing new data to investigate stroke,
dementia, osteoporosis, arthritis, diabetes, eye disease, cancer and the genetic patterns of many
common diseases.
Two generations of study participants and dedicated researchers from the National Heart , Lung,
and Blood Institute (NHLBI), Boston University, other area universities and collaborators around
the world have revolutionized the way we view, treat and prevent cardiovascular disease and a
host of other disorders. Investigators hope to add a third generation of participants in the near
future.
Before Framingham, most physicians believed that atherosclerosis was an inevitable part of the
aging process and were taught that blood pressure was supposed to increase with age enabling
the heart to pump blood through an elderly person's narrowed arteries.
Before Framingham, the notion that scientists could identify and individuals could modify "risk
factors" ( a term coined by the study) tied to heart disease, stroke and other diseases was not
part of standard medical practice.
The majority of physicians did not understand the relationship, for example, between high levels
of serum cholesterol and heart attacks. Many did not believe that modifying certain behaviors
could enable their patients to avoid or reverse the underlying causes of serious heart and
vascular conditions.
forschungsmethodologie 35
Social epidemiology: The Whitehall
Study
forschungsmethodologie 36
Page 18
The Contergan Disaster
•
•
•
•
Thalidomid ist eine chemische Verbindung, die in 2
stereochemischen Formen auftritt. Beide Formen
verhalten sich in ihrem räumlichen Bau zueinander wie
die Hände eines Menschen (bei der linken Hand steht
der Daumen rechts, und bei der rechten Hand zeigt der
Daumen nach links). Bei der chemischen Synthese von
Contergan entsteht sowohl rechts- als auch
linksbebautes Thalidomid. Ein Gemisch dieser beiden
gespiegelten Formen nennt man Racemat.
Pharmazeutisch gesehen war Contergan ein Derivat
des bewährten Schlafmittels Doriden. Doriden
wiederum ist ein Abkömmling der berühmt-berüchtigten
chemischen Gruppe der Barbiturate. Bei diesen
Schlafmitteln, inclusive dem Doriden, spielt diese
Stereochemie eine enorme Rolle. Es ist oft notwendig,
eine der beiden molekularen Spiegelformen zu
entfernen oder gar nicht erst entstehen zu lassen.
Allerdings war beim Doriden Racemat nur eine der
beiden Komponenten biochemisch aktiv.
Insofern wurde auch die Aufnahme und der Abbau des
verwandten Thalidomids im Körper untersucht. Auch
hier wirkte nur eine der Spiegelformen als Schlafmittel,
die zweite Form schien keine Wirkung zu haben. Die
für unwichtig gehaltene Spiegelform des Contergans,
die zu 50% in jeder Tablette enthalten war, besass
allerdings eine in den unzulänglichen Test nicht
entdeckte Hauptwirkung auf die embyonale Zellteilung.
Diese als Zellteilungsgift wirkende Komponente soll
heute als Krebsmittel und in der Leprabekämpfung
eingesetzt werden.
Die Wissenschaftler bei Grünenthal erkannten die
bestehende Gefahr nicht. Es haette natürlich auch die
Möglichkeit gegeben, die psychotrope d.h.
einschläfernde Form von Thalidomid in Reinform auf
den Markt zu bringen.
forschungsmethodologie 37
The FDA and Contergan
• During the Kefauver hearings, FDA
received an NDA for Kevadon, the
brand of thalidomide that the William
Merrell Company hoped to market in
the U.S.
• Despite ongoing pressure from the
firm, medical officer Frances Kelsey
refused to allow the NDA to become
effective because of insufficient safety
data.
• By 1962 thalidomide's horrifying
effects on newborns became known.
Even though Kevadon was never
approved for marketing, Merrell had
distributed over two million tablets for
investigational use, use which the law
and regulations left mostly unchecked.
• Once thalidomide's deleterious effects
became known, the agency moved
quickly to recover the supply from
physicians, pharmacists, and patients.
For her efforts, Kelsey received the
President's Distinguished Federal
Civilian Service Award in 1962, the
highest civilian honor available to
government employees.
forschungsmethodologie 38
Page 19
Thalidomid heute
• Nachdem der Wirkstoff Thalidomid auf Grund des
Conterganskandals jahrelang als Arzneimittel geächtet
galt, wird die Substanz heute z. B. für die Behandlung
von Lepra verwendet. Als weitere Anwendungsgebiete
werden zur Zeit die Moeglichkeiten als Rheumamittel
und als Antikrebsmittel untersucht.
• Der Einsatz in der Krebstherapie beruht auf der
antiangiogenetischen (Hemmung der Neubildung von
Blutgefaessen und dadurch Hemmung des
Krebswachstums) Wirkung des Thalidomids.
forschungsmethodologie 39
Thalidomide revival
Multiple myeloma first line
Thalidomide use in oncology
forschungsmethodologie 40
Page 20
The birth of good clinical practice
(GCP)
ICH Definition:
A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides assurance
that the data and reported results are credible and
accurate, and that the rights, integrity and
confidentiality of trial subjects are protected
forschungsmethodologie 41
Sir Archibald Cochrane (1909 -1988)
forschungsmethodologie 42
Page 21
National Institute of Clinical
Excellence
forschungsmethodologie 43
Far better an approximate answer
to the right question, which is often
vague, than an exact answer to the
wrong question, which can always
be made precise.
Tukey JW, 1962
forschungsmethodologie 44
Page 22
Forschungsmethodologie
Thomas D. Szucs MD MBA
forschungsmethodologie 45
Scientific method
forschungsmethodologie 46
Page 23
Francis Bacon (1561-1626)
entwarf gegenüber der
aristotelischscholastischen
Philosophie und
Wissenschaft ein neues
Konzept der Wissenschaft
auf der Grundlage von
Beobachtung und
Experiment im Gegensatz
zur klassischen Methode
der Spekulation, wodurch
er zum Wegbereiter der
modernen
Naturwissenschaften und
Vorläufer des englischen
Empirismus wurde
forschungsmethodologie 47
Sir William Osler
(1849-1919)
Der berühmte amerikanische Gehirnchirurg H. Cushing beschreibt ihn - "A man
with a cultivated peace of mind, serenity - the philosophy of Marcus Aurelius".
forschungsmethodologie 48
Page 24
Occam’s Razor
Entia non sunt multiplicanda praeter necessitatem
(Entities must not be multiplied beyond necessity)
William of Occam (1285-1389) English Philosopher
For most statistical models employed, you will find that until
evidence is accrued to suggest otherwise, it is assumed that the
treatment effect is additive on the scale of measurement
chosen: raw values, logs and so forth.
Moral: be very careful before you go hunting for so-called
responders and non-responders.
People who do this should publish in the Journal for
Irreproducible Results.
forschungsmethodologie 49
forschungsmethodologie 50
Page 25
Two types of logic
Observations
Infer
Predict
Deduction
Induction
General theories
forschungsmethodologie 51
Physiology of Research
How Does it Work?
Truth in the
Truth in the
Findings
inference
inference
Universe
Study
in the Study
Research
Question
Study
Plan
design
External
Validity
implement
Actual
Study
Internal
Validity
Hulley & Cummings: Designing Clinical Research
Page 26
forschungsmethodologie 52
Ziel der Wissenschaft
Wahrheit
Beobachtung
Hypothese
Erkenntnis
Gesetz
Experiment
Theorie
forschungsmethodologie 53
Erkenntniszuwachs
• Neue Erkenntnisse schaffen
• frühere Erkenntnisse widerlegen
• Kontroverse Erkenntnisse klären
• Impulse für neue Forschung geben
forschungsmethodologie 54
Page 27
Quest for knowledge
3 Categories
Experience
Reasoning
Research
forschungsmethodologie 55
Scientists
•
Are essentially doubters, who maintain a highly
skeptical attitude toward data of science
•
Are objective and impartial
•
Deal with facts not values
•
Are not satisfied with isolated facts but seek to
integrate and systemize their findings
Ary, Jacobs & Razavieh (1990)
forschungsmethodologie 56
Page 28
Characteristics of a sound theory
•
A theory should be able to explain the observed facts
relating to a particular problem; it should be able to
explain the „why“ concerning phenomena under
consideration
•
A theory should be consistent with the observed facts and
with the already established body of knowledge
•
A theory should provide means for verification
•
A theory should stimulate new discoveries and indicate
further areas in need of investigation
forschungsmethodologie 57
„Klug zu fragen ist schwieriger als
klug zu antworten“
Persisches Sprichwort
forschungsmethodologie 58
Page 29
Leitlinien und ethische Grundsätze der
Wissenschaft
• Originalität
• Skepsis
• Öffentlichkeit
• Distanziertheit
• Anonymität
• Freiwilligkeit
• Urheberschaft
• Aufklärung
forschungsmethodologie 59
Grundbegriffe der Wissenschaftstheorie
• Problem
• Methode
• These
• Hypothese (Vermutung)
• Theorie
• Modelle
• System
• Paradigma
forschungsmethodologie 60
Page 30
Research types in health
• Research: investigation and experimentation aimed at discovery,
interpretations, and application of scientific data
• Basic science research: studies that pursue knowledge about the most
fundamental processes of life, such as how cells work
• Clinical science research: studies involving humans, usually carried out
in hospital or clinical settings, aimed at understanding the diagnosis
and treatment of diseases and disorders
• Health policy research: studies of the health care system and health
policy-making processes
• Health services research: studies of the organization, delivery, and
financing of health care
• Pharmaceutical research: basic science studies related specifically to
the discovery, development, and use of drugs
• Translational science research: studies involving the translation of basic
science research findings into applications that benefit people forschungsmethodologie
61
Research methodologies in the
health sciences
1. Experimental research
2. Survey, interview and observational research
3. Evaluation research
4. Historical research
forschungsmethodologie 62
Page 31
Selection of problem
1.
Interest
2.
Operability
3.
Scope
4.
Theoretical and practical values
5.
Health paradigm
6.
Values of the researcher
7.
Research methodology
8.
Reactivity
9.
Unit of analysis
10. Time frame
11.
Budget
forschungsmethodologie 63
The research process
1.
Selecting a problem
2.
Formulating hypotheses
3.
Reviewing the literature
4.
Listing the measures
5.
Describing the subjects
6.
Constructing a research design
7.
Constructing and identifying measurement devices
8.
Analysis of data
9.
Generating conclusions
10. Writing the report of research
forschungsmethodologie 64
Page 32
The research hypothesis
1. Should be stated clearly and concisely
2. Express the relationship between two or
more variables
3. Should be testable
forschungsmethodologie 65
Experiment: 3 Schritte
1. Schritt
2. Schritt
3. Schritt
Planung
Durchführung
Auswertung
forschungsmethodologie 66
Page 33
Planung des Experiments
• Formulierung der Frage, die durch das
Experiment beantwortet werden soll
• Ausdenken des Experimentes
• Festlegung der Grössen, die verändert
werden oder unverändert werden sollen
• Bedenken möglicher Fehlerquellen,
Störfaktoren und Einflüsse
forschungsmethodologie 67
Durchführung des Experimentes
• Aufbauen der experimentellen Anordnung
- Auswahl der Messgeräte
- Erzwingen der gewünschten Experimentierbedingungen
• Durchführung der Beobachtungen oder Messungen
entsprechend Plan
• Protokollieren der Beobachtungs- und Messergebnisse
forschungsmethodologie 68
Page 34
Auswertung des Experimentes
• Verarbeitung der Beobachtungs- bzw. Messergebnisse
• Erkennen der Zusammenhänge
• Prüfung der Zusammenhänge
• Formulieren des Ergebnisses
- Bearbeitung der Frage
- Schlussfolgerung
• Ermittlung möglicher Fehler
Fehlerbetrachtung
forschungsmethodologie 69
Kriterien wissenschaftlicher
Fragestellungen
Originalität:
Ist Thema neu?
Relevanz
Ist Thema wert, bearbeitet zu werden?
Stand der Forschung
Ist die Literatur durchforstet und
ausgewertet?
Ressourcen
Sind genügend Ressourcen vorhanden?
Forschungsstrategie
Welche Strategie wird gefahren:
Experiment, Theorie oder Studie
Qualität der Fragestellung
Ist die Fragestellung widerspruchsfrei und
operationalisierbar?
forschungsmethodologie 70
Page 35
Richtwerte Manuskriptumfang
Dissertation
5
2-3
10
10-20
10
1-2
10
2
ca. 65
Individuell
Titel
Einleitung
Material und Methode
Ergebnisse
Diskussion
Zusammenfassung
Literaturverzeichnis
Lebenslauf, Dank
Summe
Anhang
Zeitschriftenartikel
1
2
4
5
3
1/2
2
18
forschungsmethodologie 71
Elemente Publikationsmanuskript
• Methods
– Design
– Subjects/Ethics
– Data collection/Intervention
– Outcomes
– Statistical
• Results
• Discussion
– Conclusions
– Cite literature that concludes
conclusions
– Cite literature contradicting
the study data
– Explain discrepancies
– Limitations
– Implications
forschungsmethodologie 72
Page 36
The scientific approach 1
•
Research is directed forward the solution of the problem.
•
Research emphasizes the development of generalizations,
principles or theories that will be helpful in predicting future
occurrences.
•
Research is based on observable experience or empirical
evidence.
•
Research demands accurate observation and description.
•
Research involves gathering of new data from primary or
first-hand sources or using existing data for a new purpose.
•
Although research activity may at times be somewhat
random and unsystematic, it is more often characterized by
carefully designed procedures, alwaysContinuing
applying
rigorous
next slide
analysis.
forschungsmethodologie
73
The scientific approach 2
•
Research requires expertise.
•
Research needs to be objective and logical, applying
every possible test to validate the procedures employed,
the date collected, and the conclusions reached.
•
Research involves the quest for answers to unsolved
problems.
•
Research is characterised by patient and unhurried
activity.
•
Research is carefully recorded and reported.
•
Research sometimes requires courage.
forschungsmethodologie 74
Page 37