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Metodologia cercetrii tiinifice

Ipoteza de lucru Organizarea studiului Tipuri de studii

Corin Badiu, 2007

Obiective
Dobandirea abilitatilor de cercetare Redactarea unui protocol de 10 pagini pentru un studiu real Analiza altor studii (peer review)

Tipuri de Studii
Nu sunt cea mai buna alegere pentru acest curs Studii fundamentale: molecule, celule, soareci Cost-eficienta, meta-analize Cercetare calitativa Ideal

Un studiu observational (sau experiment) ce implica pacienti

Sectiuni ale protocolului de studiu


Ipoteza de lucru Semnificatia (fondul) Designul studiului Populatia de studiu si recoltarea datelor; controlul de calitate al datelor Variabile si masuratori Analiza statistica a datelor Etica cercetarii medicale

Ipoteza de lucru
Toate studiile incep cu o problema, intrebare fara raspuns Scopul este alegerea unei intrebari de cercetare relevante, ce poate fi transformata in proiect

Problema studiului
Format pentru un studiu descriptiv

Intr-o populatie de [populatie de studiu ], care este prevalenta (sau media, mediana, etc.) [variabila dependenta]?

Majoritatea studiilor au mai mult decat o problema de evaluat si rezolvat Protocolul de cercetare deriva din problema studiului

Problema studiului
Format uzual (studii analitice):
Intr-o populatie de [populatie de studiu], exista o asociere intre [variabila dependenta] cu [variabila independenta]?

Identificati problema studiului enuntata in rezumat


Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children. We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a randomized, double-blind study in Soweto, South Africa. At 6, 10 and 14 weeks of age, 19,922 children received the 9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin (CRM197), and 19,914 received placebo
Klugman KP, Madhi SA, Huebner RE, et al. A trial of 9-valent pneumococcal conjugate vaccine in children with and without HIV infection. N Engl J Med 2003; 349:1341-8.

Intr-o populatie de [populatie de studiu], exista o asociere intre [variabila dependenta] si [variabila independenta]?

In a population of South African infants is immunization with a 9-valent pneumococcal conjugate vaccine associated with invasive pneumococcal disease?

Originile unei probleme de cercetare


Cercetarea literaturii

Discutia problemelor din literatura

A fi deschis la idei si tehnici noi

Importanta invatarii

Imaginatia

Caracteristicile unui studiu FINER


Fezabil Interesant pentru investigator Nou Etic Relevant

Caracteristicile FINER
Criterii de fezabilitate

Numar adecvat de subiecti Expertiza technica adecvata Realizabil ca resurse de timp si bani Resurse umane calificate adecvat

Caracteristicile FINER
Criterii de interes

Studii cu impact populational Detalierea a noi mecanisme de boala Studii de eficienta terapeutica pentru metode noi

Caracteristicile FINER Criterii de noutate


Confirma sau anuleaza cercetari anterioare
Extinde cercetari anterioare Furnizeaza noi date

Caracteristicile FINER Criterii de etica


Consimtamant informat !!! Protejeaza pacientii sau NU ii expune unui risc suplimentar Excluderea imediata / oprirea studiului in cazul unor efecte adverse severe

Caracteristicile FINER Criterii de relevanta


Pentru cunoasterea stiintifica Pentru clinicieni, sanatatea publica sau politicile de sanatate Pentru directii de cercetare viitoare

Probleme si solutii: Planul nu este FINER


Nefezabil

Prea larg Prea putini pacienti disponibili Metode sofisticate, peste abilitatile dovedite de investigator Prea scump

Fara interes, noutate sau relevanta Evaluare etica inadecvata

Probleme si solutii:
Planul nu este fezabil
Prea larg

Un set mai mic de variabile Se delimiteaza mai mult domeniul Extinde criteriile de includere Schimba criteriile de excludere Adauga alte surse de subiecti Extinde durata de inrolare Foloseste strategii de scadere a lotului

Insuficienti subiecti disponibili


Probleme si solutii: Planul nu este fezabil


Metode in afara abilitatilor investigatorului

Colaborare cu colegi cu aptitudini Consultarea de experti si reluarea literaturii pentru metode alternative Invata si practica aptutidinile cerute de studiu

Prea scump

Scade costurile designului de studiu


Mai putini subiecti si masuratori Detaliu mai mic al masuratorii Mai putine vizite de urmarire

Probleme si solutii: Planul nu este FINER


Neinteresant, vechi sau irelevant

Consulta mentorul Modifica problema cercetata

Abordare etica nesigura

Consulta comitetul de etica Modify the research question

Probleme and solutii


Planul de studiu este vag

Rescrie planul de cercetare mai amanuntit

Detaliaza din planul de studiu


Cum vor fi selectati subiectii si lotul martor Cum vor fi masurate variabilele

Probleme si solutii: exemple


Ce relatie exista intre depresie si sanatate? Consumul de carne rosie determina cancer? Scaderea colesterolului seric previne boala cadiaca ischemica?

Anatomia Cercetarii Clinice

Fiziologia cercetarii clinice:


Cum are loc?
Se folosesc masuratorile intr-o proba / esantion /lot de studiu pentru a extrage inferente despre fenomene (variabile) intr-o populatie

Tipuri de variabile
Variabile de confuzie*

Predictor*

Rezultat

Modificatori ai efectului*
*Considerate general ca expunere la factori de risc

Problema de studiu
In studii descriptive:
Intr-o populatie de [study population], care este prevalenta [outcome variable]? In studii analitice : Intr-o populatie de [study population], este [predictor variable] asociata cu [outcome variable]?

Tipuri de studii clinice


Studii fara variabile

Studii de caz, serii de cazuri, editoriale, opinii / comentarii, rapoarte review Studii descriptive

Studii cu o singura variabila

Studii cu 2 variabile

Experimente Studii observationale Meta-analize si review-uri sistematice

Ierarhia tipurilor de studii clinice

Descriptive studies Experimental studies

Analytic studies Observational studies

Cohort

Case-control

Cross-sectional

Variabile

Variabila predictor (independenta)

Variabila rezultat (dependenta)

An important methodology question which is implicitly related to study objectives. Imperative to decide on the study design before data collection and analysis

Study Design is important because it serves the primary purpose of maximizing study validity, in particular minimizing biases.

What study designs have you come across?


Various designs differ in their vulnerability to threats to study validity, a strong design being less vulnerable than weaker designs.
However, strength tends to trade off with cost. Stronger design is generally more costly to do.

Factors influencing selection of study design

1. Objective of the study- research questions 2. Occurrence of disease / exposure -rare/ common 3. Ethical issues 4. Resources- money, manpower, machine

What study design is most appropriate?


Do cell phones cause brain cancer?
Does diet affect breast cancer risk? Does passive smoking cause lung cancer?

Classifications of research design


1. Experimental/ Quasi-experimental or observational 2. Directionality of the study in relation to exposure and disease occurrence 3. Quantitative /qualitative

Hulleys Research Question (1993)


Ar trebui sa primeasca substitutie cu estrogeni femeile postmenopauza?

Hulleys Research Question (1993)

Ar trebui sa primeasca substitutie cu estrogeni femeile postmenopauza?

Subiecti: femei postmenopauza Predictor: estrogeni Rezultat: ?

Ameliorarea problemei de cercetare

Tratamentul cu estrogeni previne accidentul coronarian la femei postmenopauza?


Subiecti:femei postmenopauza Predictor: tratament cu estrogeni vs no treat Rezultat: accident coronarian

FINER?

Fezabil Interesant Nou Etic Relevant

Seven basic study designs :


Randomized controlled trial 2. Cohort study 3. Case-control study 4. Sample survey or cross sectional study 5. Ecologic or trend study 6. Case report or series 7. Qualitative research
1.

Ncesitatea desing-ului
Trial clinic randomizat

Puncte finale Interes primar

Studiu observational

Cross-sectional Case control Cohorta

1.Experimental/Interventional StudiesRandomized controlled trial


Evaluate new forms of therapy and prevention New drugs and other treatment of disease New medical and health care technology New methods of primary prevention New programs for screening and early detection of disease New ways of organizing and delivering health services ( community trial ) Impact of new policies in health care and health care financing ( community trial )

Randomized controlled trial Strongest design- randomization, minimize selection bias ( but not completely) Not ethical- harmful intervention, poor clinical outcome Not practical- rare disease, rare outcome Study subjects participation is crucial

Randomized Controlled Trial


Elements
Selection of subjects
-similar features -inclusion/exclusion criteria

Design

Defined population
Randomization

Allocation of subjects

Intervention

New treatment

Current treatment /no treatment

Outcome Data collection

Improved

Not improved

Improved

Not improved

Masking (blinding)

RCT
Blinding

Double- subjects & investigators Single subjects (placebo effect) Triple blind- subjects & investigators & statisticians

Outcome/endpoint

improvement ( desired effect) and side effects must be explicitly defined measured comparably in all study groups

Multi-centre trial Comply with GCP requirements Clinical trials/ community trials Results of RCT- benchmark- good clinical practice (GCP) , clinical governance, treatment protocol.

Types of RCT: Superiority or equivalence trials Parallel-most common

A B

Cross over
-

Planned washout period

randomized
- Unplanned

A B
randomized

B A
Medical
Require surgery No surgery

Surgical
Refuse surgery Surgery

Analyze outcome by intention to Rx

Limitation
1. ? effective in uncontrolled community 2. consent refusal- automatic selection ( people who participate are different from those who do not) 3. Non compliance ( people who are compliant are very different from those who are not) - drop-outs: no adherence to experimental regimen, loss to f/u -drops-in: no adherence to control regimen 4. Compliance -Need monitoring 5. Most costly

Observational studies

Cohort study 2. Case-control study 3. Cross sectional study 4. Ecologic or trend study 5. Case report or series 6. Qualitative research Direction, timing , +/- control
1.

Studiu de cohorta
Subiecti

5000 femei cu varsta 55+ ani estrogeni post-menopausal? Incidenta accidentelor coronariene dupa 5ani de terapie

Factor predictor:

Outcome:

When is a cohort study warranted ?


When there is good evidence of an association of the disease with a certain exposure When exposure is rare and incidence of disease among exposed is frequent When the time between exposure and disease is short When the investigator has a long life expectancy!

Definition
Cohort: any designated group of individuals who are followed or traced over a period of time Free of the outcome at the beginning of follow-up (population at risk) Usually defined or divided by exposure status

Population at Risk
All subjects within a cohort must be free of the outcome at the start of the followup period All subjects must be at risk for developing the disease (population at risk)

Outcome Measure
Closed Cohort

Incidence Rate Incidence Proportion (Risk)


provided there is limited impact due to competing risk and loss to follow-up

Open Cohort

Incidence Rate

Merits of Prospective VS. Restrospective Cohort Studies


Prospective Cohort Study

Retrosepective Cohort Study

Better control of the quality and quantity of the data


less potential for bias

Poorer control of the quality and quantity of the data


greater potential for bias

More time consuming More expensive

Less time consuming Less expensive

Loss to Follow-up
Problem, especially if lost subjects are at higher/lower risk for developing the outcome compared to other subjects

even worse if this problems is different with comparison groups

< 60% follow-up is generally regarded with skepticism

Analysis of data-cohort study

Start with exposure h/o, then follow to see Incidence rate whether Disease + Disease total
of disease

Exposed +

a+b

a/a+b

Exposed -

c+d

c/c+d

Analysis of data-cohort study


(cont)

Absolute risk= incidence of disease cases in exposed group/total population Relative risk= incidence of dis among E+ incidence of dis among E Odd ratio = ad/bc

Limitations
Some exposure can change over time e.g. aging, life style ( diet, smoking pattern), exposure to pharmaceutical agents, air pollution Changes on method over time- disease identification Prospective - follow-up, thus long period Costly Potential bias

selection bias ( who has been exposed and who has not ) information bias historical data bias in outcome assessment non-response and loss to f/u analytical bias

Cross-sectional design
Subiecti

2000 femei varsta 55+ ani

Predictor:

Tratament post-menopausal cu estrogeni?

Rezultat:

Istoric de accident coronarian?

Sample survey or cross sectional study :


It is a survey of the frequency of disease and other characteristics in a defined population at one particular time. Focus on describing a state or process at a fixed time.
Suitable for describing prevalence and distribution of heath problem in a community. (prevalence or health survey).

Sample survey or cross sectional study : - cont

In clinical research, used in :

Describing disease presentation (spectral description study) Diagnostic test accuracy study Quality of care assessment.

Generally efficient but large scale community survey can be expensive. Sometimes survey data given causal interpretation (pseudo-longitudinal) but liable to error, caution.

Advantages of Cross Sectional Study Design


One stop shopping Less expensive Potentially can detect effect of exposure that do not vary over time

Disadvantages of Cross Sectional Study Design


May not detect associations that for diseases with short duration that have cyclic or seasonal trends (e.g. some infectious diseases) May require over-sampling of low prevalence exposure or disease groups

Design Case-control
Subiecti / femei la menopauza

Cazuri: 100 femei cu accident coronarian Controale: 100 femei fara patologie cardiaca

Predictor:

Au luat estrogeni post-menopauza?

Rezultate:

Cazuri vs controale

Controls
Case Control Studies compare exposure history of cases and controls Controls provide exposure distribution of exposure (exposed and unexposed cohorts) in source population that gave rise to the cases in the study Biggest Problem: Identifying an appropriate control group

Sources for Controls


Population Controls Neighborhood Controls Random-Digit Dialing Hospital-Based Controls

Nested Case Control Studies


Every Case Control Study can be thought as being conducted within a cohort study

Cases represent the outcomes of the cohort Controls provide estimate of exposure distribution of cohort

Traditionally, Nested Case Control Study usually refers to study that are conducted within the experience of a well-defined cohort study

2x2 Table
Case a c M1 Control b d M0

Exposure + Exposure Total

OR = (a/c) / (b/d) (a/c) / (K1/K0) IRR

Hospital-Based Controls
Most appropriate for hospital-based cases with ill-defined catchment area as source population Often chosen from diagnostic groups not thought to be related to the exposure

better to choose more than one diagnostic group for controls minimizes impact of a poor choice

Hospital-Based Controls
History of diagnosis for different condition related to exposure is not grounds for exclusion

Some cases may have the same history


catchment area for control diagnosis is same as catchment area for cases control reflect exposure distribution for source population of cases

Assumption:

Comparison of Case Control and Cohort Studies


Primary Difference:

Cohort Study involved complete enumeration of the source population Case Control Study involved a sample (controls) of the source population
Case Control Studies are modified Cohort Studies

When is a case control study warranted?


When there is good evidence of an association between a certain exposure and the disease When disease is rare and exposure is frequent among exposed Advantage:

Cost- relatively inexpensive Sample size relatively small

Analysis of data -case control study


Begin with cases with disease and controls without
disease, then measure past exposure Disease + Disease total

Exposed + Exposed Proportion of exposed

a
c a/a+c

b
d b/b+d

a+b
c+d

Odd ratio= a/a+c / b/b+d= ad/bc

Limitation
Selection of appropriate controls Recall bias - Human ability to recall - Recall bias (Case may remember their exposure more than controls do)

Etic?
Echivalenta (nu este sigur daca domina beneficii sau riscuri)

Beneficii ale terapiei de substitutie Scad simpotomele de climax ? Preventia fracturilor ? Preventia BCI ? Preventia Alzheimer ? Cresterea calitatii vietii

Riscuri ? trombo-embolism pulmonar ? Cancer mamar

Relevant?
Estrogeni / estroprogestative Decizia afecteaza o mare parte din populatie

TRECUT
A primit HRT?

PREZENT
Cancer mamar

No

Yes Cazuri

No

Yes Controale

Fara cancer de san

Case report or series :


Description of one or several cases in which no attempt is made to answer specific hypotheses or to compare results with another group of cases.

classical clinical study; its value probably under rated (Pickering Lancet 19##)

Case report or series


Description of one or several cases in which no attempt is made to answer specific hypotheses or to compare results with another group of cases No control

Classical clinical study Its value probably under rated

Case Reports and Case Series


Example: investigators at a single institution note that a small number of patients treated with a alternative (complementary) therapy exhibit longer survival and better survival than "expected" Example: investigators notice a higher than expected incidence of a cancer in a community Example: investigators note a common occupational exposure in a series of patients with a rare cancer

Case Reports and Case Series


Problems: lack of a control group
no measure of effect no formal statistical analysis

Advantages: hypotheses generators

Case Series With Literature Controls


Compare outcomes of case series to "expected" results based on existing records (e.g. published results, national incidence/mortality rates) Problems: lack of comparability

Confounding
Healthy Worker Effect

Bias

5. Ecologic or trend study :


Group based study
Unit of observation is a group eg country, state etc.

Observed effect difficult to interpret at individual level (ecologic fallacy). Otherwise efficient to do.

5. Ecologic or trend study :


Group based study, unit of observation is a group e.g. country, state etc. Ignore variability between individuals May ascribe to members characteristics they do not possess as individuals

Age standardized death rate per 1000 Quantity of salt sold at Henan province in China

Qualitative research :
Development of concepts which help us to understand social phenomena in natural settings, giving due emphasis to the meanings, experiences, and views of all the participants It does not primarily seek to provide quantified answers to research questions Particularly useful for explaining complex phenomena not amenable to quantitative research

Qualitative research : - cont


It has an important role in medical research because health care deals with people and people are more complex than the subjects of the natural sciences. There is a whole set of questions about human interaction that we need answers to. Obvious areas of application are doctorpatient relationship, treatment compliance, clinical decision making process, issues on health service organisation and policy issues.

Qualitative research-contd:

Development of concepts which help us to understand social phenomena in natural settings, giving due emphasis to the meanings, experiences, and views of all the participants
Useful for explaining complex phenomena not amenable to quantitative research Approaches- Focus group, observation, interview, diary

Obvious areas of application are doctor-patient relationship, treatment compliance, clinical decision making process, issues on health service organization and policy issues

Conceptia unui plan de cercetare


1. Definitia problemei
2. Dezvoltarea planului de cercetare

Lista elementelor studiului

Identificarea referintelor publicate

3. Introducerea (fondul problemei) si semnificatia sa (istoric al cercetarilor anterioare, motivatie, importanta)

Plan de studiu
Problema cercetata Semnificatie (background) Designul studiului Populatia de studiu si esantionarea Variabile si masuratori Elemente statistice
Aspecte etice Controlul calitatii si evaluarea datelor

Problema principala a studiului? De ce este important? Cum se va face studiul ?


Care sunt subiectii si cum sunt selectati? Ce masuri vor fi luate? Dimensiunea lotului si analiza? Exista probleme etice? Cum se asigura controlul calitatii datelor si analizei acestora?

Fond si semnificatie
Bazat pe experienta
Atentie la idei noi Atentie la tehnologii noi

Sa fim constienti despre punctele forte si slabe ale cercetarilor anterioare similare, proprii sau de literatura Sa stim ce dorim sa comunicam / confirmam la final

Fondul si semnificatia problemei / importanta pentru protocol


Asemanator cu introducerea la un articol Introduce cercetarea propusa, in context Descrie motivatia studiului Ce se stie despre topic De ce este problema propusa, importanta? Ce tip de raspuns asteptam de la studiu?

Fond si semnificatie
Citarea cercetarilor relevante anterioare (inclusiv propriile date)
Indica punctele forte si slabe ale studiilor anterioare, ca si intrebarile ramase fara raspuns. Arata cum vor fi folosite rezultatele studiului propus pentru rezolvarea neclaritatilor si influentarea politicii de sanatate sau practicii clinice

Gasirea literaturii adecvate


End note, Reference manager Verifica formatul referintelor conform instructiunilor pentru autori si sunt incluse pe masura ce se scrie protocolul Se pastreaza copii ale tuturor referintelor PubMed: www.ncbi.nlm.nih.gov Comunicari personale (cine si cand) Date nepublicate (Cel mai bine se evita)

Gasirea literaturii adecvate


End note, Reference manager Verifica formatul referintelor conform instructiunilor pentru autori si sunt incluse pe masura ce se scrie protocolul Se pastreaza copii ale tuturor referintelor PubMed: www.ncbi.nlm.nih.gov Comunicari personale (cine si cand) Date nepublicate (Cel mai bine se evita)

Fundamentele Stiintifice ale Cercetarii


mai multe principii fundamentale sunt utilizate in cercetarea stiintifica:
1.Ordinea 2.Deductia si Sansa 3.Evaluarea si Probabilitatea 4.Ipoteza

Fundamentele Stiintifice ale Cercetarii


Evaluarea si Probabilitatea(1)
Cerinta critica a efectuarii proiectului in cercetare, aceea care asigura validitatea, este evaluarea probabilitatii de la inceput pana la capat

Fundamentele Stiintifice ale Cercetarii


Ipoteza
ipotezele sunt afirmatii atent construite referitoare la un fenomen intalnit intr-o populatie ipotezele pot fi generate fie prin:
rationament deductiv rationament inductiv rezultat din observatii anterioare

Concluzii
Les sciences sont faites par additions. Nul ne commence ou acheve. Nous sommes montes sur les epaules dun geant. Nous voyons tot ce que voit le geant, et quelque chose davantage.
Guy de Chauliac, 1684