Evidence based medicine

Cum concepem un protocol de cercetareCorin BadiuUMF Carol Davila Bucuresti

Protocol de cercetareCorin Badiu, 2014

Originile unei probleme de cercetareCercetarea literaturiiDiscutia problemelor din literatura

A fi deschis la idei si tehnici noi Importanta invatariiImaginatia

Ipoteza de lucruToate studiile incep cu o problema, intrebare fara raspuns

Scopul este alegerea unei intrebari de cercetare relevante, ce poate fi transformata in proiect

Problema studiuluiFormat pentru un studiu descriptivIntr-o populatie de [populatie de studiu ], care este prevalenta (sau incidenta, mortalitatea, 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

Caracteristicile unui studiuFINERFezabilInteresant pentru investigatorNouEticRelevant

Caracteristicile FINERCriterii de FezabilitateNumar adecvat de subiectiExpertiza technica adecvataRealizabil ca resurse de timp si baniResurse umane calificate adecvat

Caracteristicile FINERCriterii de InteresStudii cu impact populationalDetalierea a noi mecanisme de boalaStudii de eficienta terapeutica pentru metode noi

Caracteristicile FINERCriterii de NoutateConfirma sau anuleaza cercetari anterioare

Extinde cercetari anterioare

Furnizeaza noi date

Consimtamant informat !!!Protejeaza pacientii sau NU ii expune unui risc suplimentarExcluderea imediata / oprirea studiului in cazul unor efecte adverse severeCaracteristicile FINERCriterii de Etica

Pentru cunoasterea stiintificaPentru clinicieni, sanatatea publica sau politicile de sanatatePentru directii de cercetare viitoareCaracteristicile FINER Criterii de Relevanta

Probleme si solutii:Planul nu este FINERNefezabilPrea largPrea putini pacienti disponibiliMetode sofisticate, peste abilitatile dovedite de investigatorPrea scumpFara interes, noutate sau relevantaEvaluare etica inadecvata

Probleme si solutii:Planul nu este FezabilPrea largUn set mai mic de variabileSe delimiteaza mai mult domeniulInsuficienti subiecti disponibiliExtinde criteriile de includereSchimba criteriile de excludereAdauga alte surse de subiectiExtinde durata de inrolare Foloseste strategii de scadere a lotului

Metode in afara abilitatilor investigatoruluiColaborare cu colegi cu aptitudiniConsultarea de experti si reluarea literaturii pentru metode alternative Invata si practica aptitudinile cerute de studiu

Prea scumpScade costurile designului de studiuMai putini subiecti si masuratoriDetaliu mai mic al masuratoriiMai putine vizite de urmarireProbleme si solutii:Planul nu este fezabil

Neinteresant, vechi sau irelevantConsulta tutoreleModifica problema cercetata

Abordare etica nesiguraConsulta comitetul de eticaModifica intrebarea / designulProbleme si solutii: Planul nu este FINER

Probleme si solutiiPlanul de studiu este vagRescrie planul de cercetare mai amanuntit

Detaliaza din planul de studiuCum vor fi selectati subiectii si lotul martorCum vor fi masurate variabilele

Anatomia Cercetarii Clinice

Componentele unui protocolStudy protocolIntroductionResultsPatients and MethodsReferencesDiscussionHypothesisReadingAims & Obj.FiguresAnalysisTablesstatisticsTextTitle & abstractRelevant background to the problemInformed consentInclusion/ exclusioncriteriaFlowchartVariabile

Sapte tipuri de studii Studii randomizat controlate Studii de cohorta Studii caz - control Studii transversale - cross sectional Studii de tendinta Case reports Cercetare calitativa - Chestionare

Ierarhia tipurilor de studii cliniceConceptie (study design) legata de obiectivele studiului.Conceptie inainte de colectarea si analiza datelorConceptia studiului este importanta intrucat permite o crestere a validitatii si reducerea erorilor.

Necesitatea desing-uluiTrial clinic randomizatPuncte finaleInteres primar

Studiu observationalCross-sectionalCaz controlCohorta

1. Studii Experimental / Interventionale - Randomized controlled trial (RCT)Evaluarea de noi metode de profilaxie si tratamentMedicamente si terapii noi pentru boliTehnologii medicale si tehnici de ingrijire noiMetode noi de preventie primaraPrograme noi de screening si detectare precoceSisteme noi de asistenta sanitara comunitara (community trial )Impactul noilor politici in sistemul de sanatate si finantarea sistemului sanitar ( community trial )

Randomized controlled trialCel mai bun design- randomizare, eroare de selectie minima (dar nu zero);Nu este etic: daca interventie poate dauna, rezultat clinic slabNu este practic boli rare, efect rar;Participarea subiectilor la studiu este cruciala.

Randomized Controlled TrialElementeDesign

RandomizareTratament nouTratament curent/no treatment Definirea populatiei

AmelioratNe amelioratAmeliorat InterventieOutcomeSelectia subiectilor - trasaturi similare - criterii includere /excludereAlocarea subiectilorColectarea datelorMasking (blinding)Ne ameliorat

Randomized Controlled TrialBlindingDouble- subjects & investigators Single subjects (placebo effect) Triple blind- subjects & investigators & statisticiansOutcome / endpointimprovement ( desired effect) and side effectsmust be explicitly defined measured comparably in all study groupsMulti-centre trialComply with GCP requirementsClinical trials/ community trialsResults of RCT- benchmark- good clinical practice (GCP) , clinical governance, treatment protocol.

Types of RCT:Superiority or equivalence trials AParallel - most common B Cross overPlanned washout period A B B A- Unplanned SurgicalMedical randomizedrandomizedRefuse surgery

Require surgery

Analyze outcome by intention to Rx

No surgery

Surgery

Limite

1. ? effective in uncontrolled community2. Informed 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

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

Cand este bun un studiu de cohorta?When there is good evidence of an association of the disease with a certain exposureWhen exposure is rare and incidence of disease among exposed is frequentWhen the time between exposure and disease is shortWhen the investigator has a long life expectancy!

Populatia la riscAll subjects within a cohort must be free of the outcome at the start of the follow-up periodAll subjects must be at risk for developing the disease (population at risk)

Studii de cohorta Prospective vs. RetrospectiveProspective Cohort StudyBetter control of the quality and quantity of the dataless potential for biasMore time consumingMore expensive

Retrospective Cohort StudyPoorer control of the quality and quantity of the datagreater potential for biasLess time consumingLess 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 subjectseven worse if this problems is different with comparison groups< 60% follow-up is generally regarded with skepticism

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 : - contIn clinical research, used in :Describing disease presentation (spectral description study)Diagnostic test accuracy studyQuality 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 DesignOne stop shoppingLess expensivePotentially can detect effect of exposure that do not vary over time

Disadvantages of Cross Sectional Study DesignMay 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

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

Case report or seriesDescription 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

ControlsCase 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

Nested Case Control StudiesEvery Case Control Study can be thought as being conducted within a cohort studyCases represent the outcomes of the cohortControls provide estimate of exposure distribution of cohortTraditionally, Nested Case Control Study usually refers to study that are conducted within the experience of a well-defined cohort study

Comparison of Case Control and Cohort StudiesPrimary 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 inexpensiveSample size relatively smallWhen is a case control study warranted?

Conceptia unui plan de cercetareDefinitia problemeiDezvoltarea planului de cercetare Lista elementelor studiuluiIdentificarea referintelor publicateIntroducerea (fondul problemei) si semnificatia sa (istoric al cercetarilor anterioare, motivatie, importanta)

Plan de studiuProblema cercetataSemnificatie (background)Designul studiuluiPopulatia de studiu si esantionareaVariabile si masuratoriElemente statistice

Aspecte eticeControlul calitatii si evaluarea datelorProblema 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?

Variabila predictor(independenta)Variabila rezultat (dependenta)Variabile

Consecventa de inregistare este VitalaSe inregistreaza acelasi tip de date Formulare tipizate pentru studiu Se completeaza integral, fara spatii libereSe transcriu in format electronic

Factori care influenteaza conceptia studiului 1. Obiectivele studiului intrebarile cercetarii2. Epidemiologia bolii / expunerii - rara / comuna3. Aspecte etice 4. Resurse- bani, oameni, infrastructura

Gasirea literaturii adecvateReference manager, End noteVerifica formatul referintelor conform instructiunilor pentru autori si sunt incluse pe masura ce se scrie protocolulSe pastreaza copii ale tuturor referintelorPubMed:http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed Comunicari personale (cine si cand)Date nepublicate (Cel mai bine se evita)

Reference managerSistem de documentare si editare a referintelor in articolFormarea unei baze de date: import din sisteme internationale, sau prin filtre (NLM medline), introducere manuala (Ins). Tipuri de baze de date: tematice (KW), abstract, autori, reviste, date, Prelucrarea bazei de date: duplicate, cautari, reference list display, link catre PM, pdf, url; copieri intre baze de date.Modulul Cite While You Write (CWYW) in Word.Alegerea si editarea stiluluiScrierea referintelor in text si lista bibliografica; schimbarea paragrafelor in text.

Sectiuni ale protocolului de studiuIpoteza de lucruSemnificatia (fondul)Designul studiuluiPopulatia de studiu si recoltarea datelor; controlul de calitate al datelorVariabile si masuratoriAnaliza statistica a datelorEtica cercetarii medicale

IMRaD + C

I. IntroducereFondul problemei, nivelul de cunoastere international /national

Conduce cititorul catre ipoteza de lucru

Descrie drumul problemei in literatura

Arata resursele disponibile si experienta anterioara care justifica abordarea problemei

Materiale / Pacienti si Metode (Sectiune Experimentala, Metodologie, Metoda)Intotdeauna descrie cele necesare cercetarii:Pacienti sau subiecti, cu structura de loturiAnimale de experientaMateriale , reactivi, instrumente, aparaturaSurse de reactivi, interval de normalIntotdeauna descrie proceduri experimentale, inclusiv calcule, procedee statisticeFoloseste ordinea cronologica (flow-chart pt experimente)

III. RezultatePrezinta rezultatele in concordanta cu loturile de studiu si metodele folosite

Include tabele, grafice, figuri, etc.

Comenteaza statistica rezultatelor (sumar)

Prezinta rezultatele in ordinea experimentelor

IV. Discutia rezultatelorReluam problema din punctul lasat la introducerePrezentam punct cu punct rezultatele studiului nostru comparativ cu cele din literaturaDiscutam rezulatele global, sustinand punctul de vedere al mesajului principal al articoluluiPrezentam capcanele si limitele studiului, comparativ cu cele din literatura

V. ConcluziiCateva paragrafe

Rezuma scopul studiului si raspunsul pe care il da la intrebarea initiala

Deschid linia orizontului

Les sciences sont faites par additions ! Nul ne commence ou acheve.Nous sommes montes sur les epaules dun geant.Nous voyons tout ce que voit le geant, et quelque chose davantage.

Guy de Chaulliac, 1564

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