Corin Badiu, 2007

Metodologia cercetMetodologia cercetăării rii şştiintiinţţificeifice

Ipoteza de lucruOrganizarea studiului

Tipuri de studii

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

• Format uzual (studii analitice):

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

Problema studiului

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.

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

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

Originile unei probleme de cercetare

• Cercetarea literaturii Discutia problemelor din literatura

• A fi deschis la idei si tehnici noi Importanta invatarii

• Imaginatia

Caracteristicile unui studiuFINER

• Fezabil

• Interesant pentru investigator

• Nou

• Etic

• Relevant

Caracteristicile FINERCriterii de Fezabilitate

• Numar adecvat de subiecti

• Expertiza technica adecvata

• Realizabil ca resurse de timp si bani

• Resurse umane calificate adecvat

Caracteristicile FINERCriterii de Interes

• Studii cu impact populational

• Detalierea a noi mecanisme de boala

• Studii de eficienta terapeutica pentru metode noi

Caracteristicile FINERCriterii de Noutate

• Confirma sau anuleaza cercetari anterioare

• Extinde cercetari anterioare

• Furnizeaza noi date

• Consimtamant informat !!!• Protejeaza pacientii sau NU ii expune unui risc

suplimentar• Excluderea imediata / oprirea studiului in cazul

unor efecte adverse severe

Caracteristicile FINERCriterii de Etica

• Pentru cunoasterea stiintifica

• Pentru clinicieni, sanatatea publica sau politicile de sanatate

• Pentru directii de cercetare viitoare

Caracteristicile FINERCriterii de Relevanta

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

• Insuficienti subiecti disponibili Extinde criteriile de includere Schimba criteriile de excludere Adauga alte surse de subiecti Extinde durata de inrolare Foloseste strategii de scadere a lotului

• 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 fezabil

• Neinteresant, vechi sau irelevant Consulta mentorul Modifica problema cercetata

• Abordare etica nesigura Consulta comitetul de etica Modify the research question

Probleme si solutii:Planul nu este FINER

Probleme si 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

Predictor* Rezultat

Variabile de confuzie*

Modificatori ai efectului*

Tipuri de variabile

*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 cu o singura variabila Studii descriptive

• Studii cu ≥2 variabile Experimente Studii observationale Meta-analize si review-uri sistematice

Ierarhia tipurilor de studii clinice

Descriptive studies

Experimental studies

Cohort Case-control Cross-sectional

Observational studies

Analytic studies

Conceptie (study design) legata de obiectivele studiului.

Conceptie inainte de colectarea si analiza datelor

Concepta studiului este importanta intrucat permite o crestere a validitatii si reducerea erorilor.

Variabila predictor(independenta)

Variabila rezultat (dependenta)

Variabile

    Factori care influenteaza conceptia studiuluiFactori care influenteaza conceptia studiului

  1. Obiectivele studiului – intrebarile cercetarii

 2. Epidemiologia bolii / expunerii - rara / comuna

 3. Aspecte etice

  4. Resurse- bani, oameni, infrastructura

Ce tip de studiu este mai adecvat?

• Telefonia mobila determina cancer cerebral?

• Dieta afecteaza riscul de cancer mamar?

• Fumatul pasiv determina cancer pulmonar?

Tipuri de study design

1. Experimental/ Quasi-experimental sau observational

2. Directia studiului in relatie cu expunerea si aparitia bolii

3. Cantitativ /Calitativ

Women's Health Initiative (1991)

Ar trebui sa primeasca substitutie cu estrogeni femeile postmenopauza?

http://www.nhlbi.nih.gov/whi/

Subiecti: femei postmenopauza

Predictor: “estrogeni”

Rezultat: ?

Ar trebui sa primeasca substitutie cu estrogeni femeile postmenopauza?

Women's Health Initiative (1991)

Ameliorarea problemei de cercetare

Tratamentul cu estrogeni previneaccidentul coronarian la femei postmenopauza?

Subiecti: femei postmenopauzaPredictor: tratament cu estrogeni vs no treatRezultat: accident coronarian

FINER?

Fezabil

Interesant

Nou

Etic

Relevant

7 tipuri de studii

1. Randomized controlled trial 2. Cohort study 3. Case-control study4. Sample survey or cross sectional

study5. Ecologic or trend study 6. Case report or series 7. Qualitative research

Ncesitatea desing-ului

• Trial clinic randomizat Puncte finale Interes primar

• Studiu observational Cross-sectional Case control Cohorta

1. Studii Experimental / Interventionale -

Randomized controlled trial (RCT)

• 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

• Cel mai bun design- randomizare, eroare de selectie minima

(dar nu zero);

• Nu este etic: daca interventie poate dauna, rezultat clinic slab

• Nu este practic – boli rare, efect rar;

• Participarea subiectilor la studiu este cruciala.

Randomized Controlled Trial

Elements Design

Randomization

New treatment Current treatment

/no treatment

Defined population

ImprovedNot

improved Improved Not improved

Intervention

Outcome

Selection of subjects -similar features -inclusion/exclusion criteria

Allocation of subjects

Data collection

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 A

• Parallel-most common B

• Cross over- Planned –washout

period

A B

B A- Unplanned

Surgical Medical randomized

randomized

Refuse surgery Require surgery

Analyze outcome by intention to RxNo surgerySurgery

Limite

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

Studii observationaleStudii observationale

1. 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

Studiu de cohorta

Subiecti 5000 femei cu varsta 55+ ani

Factor predictor: estrogeni post-menopausal?

Outcome: Incidenta accidentelor coronariene dupa 5 ani

de terapie

Cand este bun un studiu de cohorta?Cand este bun un studiu de cohorta?

• 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!

Cohorta

• 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

Populatia la risc

• All subjects within a cohort must be free of the outcome at the start of the follow-up period

• All subjects must be at risk for developing the disease (population at risk)

Studii de cohorta Prospective vs. Studii de cohorta Prospective vs. RetrospectiveRetrospective

• Prospective

Cohort Study Better control of the

quality and quantity of the data

• less potential for bias

More time consuming More expensive

• Retrosepective Cohort Study Poorer control of the

quality and quantity of the data

• greater potential for bias

Less time consuming Less expensive

Pierderea din urmarire(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

Analiza datelor – studii de cohorta

Start with exposure, then follow to see whether

Disease +

Exposed +

Exposed -

Disease - total Incidence rate of disease

a b

c d

a+b

c+d

a/a+b

c/c+d

• Absolute risk = incidence of disease cases in exposed group / total population

• Relative risk=

• Taria asociatiei (Odds ratio) = ad/bc

Analiza datelor – studii de cohorta

incidence of dis among E+incidence of dis among E-

Limite

• 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 ControlExposure + a bExposure - c dTotal M1 M0

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

• Assumption: catchment area for control diagnosis is same

as catchment area for cases control reflect exposure distribution for source

population of cases

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 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

When is a case control study warranted?

Analysis of data-case control study

Begin with cases with disease and controls without

disease, then measure past exposure Disease +

Exposed +

Exposed -

Disease - total

a b

c d

a+b

c+d

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

Proportion of exposed

a/a+c b/b+d

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 PREZENT

Cazuri

Controale

Yes

Yes

No

No

Cancer mamar

Fara cancer de san

A primit HRT?

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

Quantity of salt sold at Henan province in China

Age standardized death rate per 1000

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 doctor-patient relationship, treatment compliance, clinical decision making process, issues on health service organisation and policy issues.

Qualitative research-cont’d:

• 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 probabilitatiievaluarea probabilitatii de la

inceput pana la capat

Fundamentele Stiintifice ale Cercetarii

Ipoteza

– ipotezele sunt afirmatiiafirmatii atent construite referitoare la un fenomen

intalnit intr-o populatie

– ipotezele pot fi generategenerate fie prin:

• rationament deductivdeductiv

• rationament inductivinductiv rezultat din observatii anterioare

ConcluziiConcluzii

Les sciences sont faites par additions.Nul ne commence ou acheve.Nous sommes montes sur les epaules d’un geant. Nous voyons tot ce que voit le geant, et quelque chose d’avantage.

Guy de Chauliac, 1684