mcs tot

transcript

Corin Badiu, 2007

Metodologia cercetMetodologia cercetăării rii şştiintiinţţificeificeConcepte, necesităţi şi atitudini

Cercetarea stiintifica (1)

• joaca un rol foarte important in eforturile medicinei de a mentine starea de sanatate si de a combate bolile

• ne ajuta sa obtinem cunostinte noi si sa dezvoltam instrumente adecvate pentru a fi utilizate pe baza cunostintelor existente

• permite diagnosticarea si tratarea diverselor afectiuni

• ofera dovezi pe care sa se bazeze politicile sanitare si deciziile asupra sanatatii si dezvoltarii sistemelor de asistenta medicala

• Desi OMS si statele sale membre sunt constiente de importanta cercetarii medicale, aceasta nu a fost o prioritate in multe tari in curs de dezvoltare– lipsa metodologiei de cercetare – absenta cercetatorilor calificati – sistemul de management si coordonare a

cercetarii medicale fie:• nu a fost creat

• nu functioneaza adecvat

Procesul de cercetare

• este piatra fundamentala pentru luarea unor decizii eficiente si in cunostinta de cauza

• este parte integranta din eforturile tarilor de: – a ameliora starea de sanatate a populatiei si de – a creste eficienta sistemelor sanitare, mai

ales in conditii de transformari dramatice epidemiologice, demografice si economice, transformari care afecteaza profund sistemele sanitare

In aceste cursuri: • se vor descrie metodele de planificare

si realizare a cercetarii stiintifice: – formularea problemelor – stabilirea obiectivelor cercetarii – planificarea studiului ("designing the

study")• metode de colectare a datelor • analiza statistica a datelor

– interpretarea rezultatelor – diseminarea acestor rezultate

DEFINITII (1)

• cercetarea stiintifica este o descoperire a cunostintelor prin cautarecautare sau investigatieinvestigatie asidua sau prin experimenteexperimente avand drept scop descoperirea si interpretarea de cunostinte noi

• metoda stiintifica este un grup de tehnici si proceduri sistematice aplicate in cursul desfasurarii investigatiei sau experimentului si orientate catre obtinerea de noi cunostinte

DEFINITII (2)

• cercetarea si metodele stiintifice pot fi considerate o cale de

investigatie critica ducand la descoperirea unor fapte sau informatii

care amplifica intelegerea noastra asupra sanatatii si bolilor umane

CATEGORII ALE CERCETARII

• 1.Cercetarea Empirica si Teoretica

• 2.Cercetarea Fundamentala si Aplicata

• 3.Triunghiul Cercetarii in Domeniul

Sanatatii

1.Cercetarea Empirica si Teoretica (1)

• abordarea filozofica a cercetarii este in principal de doua tipuri:

• Empirica • Teoretica

• cercetarea in domeniul sanatatii utilizeaza in principal abordarea empirica – adica este bazata pe:

• Observatie • Experienta

– Mai putin bazata pe: » Teorie» Abstractizare

• cercetarea epidemiologica, de ex., depinde de

colectarea sistematica a observatiilor fenomenelor

legate de starea de santate care prezinta interes in

cazul unei populatii definite

• mai mult, chiar in cadrul abstractizarii prin modele matematice, NU pot fi obtinute progrese in intelegerea cauzelor si modului de aparitie a bolilor daca nu se face o

comparatiecomparatie a unor modele construite teoretic, cu ceea ce se observa concret la nivelul populatiilor

• cercetarea empirica si teoretica se completeaza

reciproc in dezvoltarea unei intelegeri a fenomenelor, in

previziunea unor evenimente viitoare si in prevenirea

unor evenimente daunatoare asupra bunastarii

generale a populatiei de interes

Cercetarea empirica

• Cercetarea empirica in stiintele

medicale poate fi:

– cantitativa

– calitativa

Cercetarea in Domeniul Medical (1) • In general cercetarea in domeniul

medical utilizeaza informatii de tip cantitativ

• In majoritatea cazurilor aceasta implica identificarea: – populatiei de interes – caracteristicilor (variabilelor) indivizilor

(unitatilor) din populatie– studierea variabilitatilor acestor

caracteristici intre indivizii din populatie

Cercetarea in Domeniul Medical (2)

• De aceea cuantificarea cercetarii empiricecuantificarea cercetarii empirice se obtine prin trei procedee numerice inter-relationate:– masurarea variabilelor – estimarea parametrilor populatiei (parametri ai

distributiei probabilitatii care surprind variabilitatea observatiilor in populatie)

– testarea statistica a ipotezelor, sau estimarea gradului in care "sansa" singura poate fi responsabila de variatia dintre indivizii sau grupurile aflate sub observatie

Cercetarea in Domeniul Medical (3) • Luarea in considerare a sansei sau

probabilitatii este substanta alcatuirii planului de cercetare (design-ului cercetarii)– mai mult decat orice, planificarea

cercetarii trebuie sa tina seama de rolul sansei pentru a asigura validitatea

– metodele statistice sunt acelea care mentin legile probabilitatii in cursul cercetarii noastre

Cercetarea in Domeniul Medical (4)

• Metodele statistice:– permit analiza si interpretarea adecvate

ale rezultatelor– statistica ofera instrumentele care permit

cercetarii medicale sa fie mai degraba empirica decat abstracta

• ea ne permite sa ne confirmam descoperirile prin continuarea observatiei si experimentului

2.Cercetarea Fundamentala si Aplicata(1)

• din punct de vedere functional cercetarea

poate fi clasificata in:

– fundamentalafundamentala (sau pura sau bazala =

"basic")

– aplicataaplicata

• cercetarea fundamentalacercetarea fundamentala – de obicei este considerata a implicata o cautare a cunostintelor fara definirea unei utilitati clare sau a unui scop specific

• cercetarea aplicatacercetarea aplicata este orientata spre o anumita problema si este directionata catre rezolvarea unei probleme existente

• Exista o controversa continua cu privire la

beneficiul relativ si contributia catre societate a

celor doua tipuri de cercetare

• unii considera ca stiinta, care depinde in mare parte de sprijinul societatii, trebuie sa se orienteze directdirect spre solutionarea unor probleme relevante ale omului, in timp ce altii pretind ca investigatia stiintifica este cea mai productiva atunci cand se efectueaza liber, fara nici o constrangere, iar cele mai mari progrese ale ale stiintei au rezultat din cercetarea pura

• in general este recunoscut faptul ca e nevoie de un echilibru sanatos intre cele doua tipuri de cercetare, societatile mai bogate si mai avansate tehnologic fiind capabile de a sustine o proportie mai mare de cercetare fundamentala decat societatile cu mai putine resurse disponibile

3.Triunghiul Cercetarii in Domeniul Sanatatii (1)

• trei trei categorii interconectate operational:– cercetarea biomedicalabiomedicala – cercetarea serviciilor de sanatateserviciilor de sanatate (serviciilor

medicale) – cercetarea comportamentalacomportamentala

• Se realizeaza astfel asa-numitul triunghi al triunghi al

cercetarii medicalecercetarii medicale

(al cercetarii in domeniul sanatatii)

• Cercetarea biomedicalaCercetarea biomedicala se preocupa in

principal de cercetarea fundamentala implicand

procesele de la nivel celular

• Cercetarea serviciilor de sanatateCercetarea serviciilor de sanatate (a serviciilor

medicale) are drept obiectiv mediul care il inconjoara e

om si care determina transformari la nivel celular

• Cercetarea comportamentalaCercetarea comportamentala se preocupa de

interactiunea dintre om si mediu inconjurator intr-o

maniera reflectand credintele, atitudinile si practicile

individului in societate

Fundamentele Stiintifice ale Cercetarii (1)

• mai multe principii fundamentale sunt utilizate in cercetarea stiintifica: 1.Ordinea

2.Deductia si Sansa

3.Evaluarea si Probabilitatea

4.Ipoteza

• 1.Ordinea (1)– Metoda stiintifica diferadifera de "bunul simt" in ajungerea

la concluzii prin utilizarea observatiei organizateobservatiei organizate a entitatilor sau evenimentelor care sunt clasificateclasificate sau ordonateordonate pe baza proprietatilor si a comportamentelor comune

Ordinea (2)– acest caracter comun al proprietatilor si

comportamentelor permite efectuarea de predictiuni care, duse la limita, devin legi

Fundamentele Stiintifice ale Cercetarii (3) • 1.Deductia si Sansa

• Gandirea, sau deductia este forta progreselor in cercetare

• in termenii logicii, aceasta inseamna ca o afirmatie sau o concluzie trebuie sa fie acceptata

deoarece una sau mai multe alte afirmatii sau premize (dovezi) sunt adevarate

• 2. Deductia si Sansa

• supozitiile, prezumtiile sau teoriile deductive pot fi atat de dezvoltate, printr-o constructie atenta,

incat sa devina ipoteze testabile

• testarea ipotezei este metoda care sta la baza avansarii cunostintelor in stiinta

• 3.Deductia si Sansa

• in dezvoltarea deductiilor s-au diferentiat doua abordari sau argumente distincte:

• deductiva

• Inductiva• 4.Deductia si Sansa

– in deductie, in mod necesar concluzia rezulta din premize, ca de exemplu in:

• silogism (toate A sunt B, toate B sunt C, de aceea toate A sunt C)

• ecuatiile algebrice

• Deductia si Sansa (5)

– deductia poate fi distinsa prin faptul ca se deplaseaza de la general la specific si NUNU permite elementele

legate de sansasansa sau nesigurantanesiguranta

– de aceea concluziile deductive sunt potrivite cercetarii teoretice

– deoarece cercetarea medicala este primordial empirica, depinde aproape in totalitate de gandirea

inductiva

– in gandirea inductiva (1)

– concluzia NU rezulta neaparat din premize sau dovezi (fapte)

– putem afirma doar ca o concluzie are o probabilitate mai mare de a fi adevarata daca premizele sunt

adevarate, adica exista posibilitatea ca premizele sa fie adevarate, dar concluziile sa fie false

– in gandirea inductiva (2)

• de aceea trebuie sa se tina seama in intregime de sansasansa

• mai departe, gandirea inductiva se distinge prin faptul ca trecetrece de la specificspecific la

generalgeneral

• 3.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

• 3.Evaluarea si Probabilitatea(2)– cele mai importante elemente (1)elemente (1) ale proiectului de

cercetare, elemente avand drept scop asigurarea integritatii probabilitatii si prevenirea bias-ului, sunt:

• esantionulesantionul sa fie reprezentativreprezentativ • randomizarearandomizarea in selectia grupurilor de studiu

• 3.Evaluarea si Probabilitatea(3)– cele mai importante elemente (2)elemente (2) ale proiectului de cercetare:

• mentinerea grupurilor de comparatiegrupurilor de comparatie sub forma grupurilor control

• realizarea principiului "dublu-orbdublu-orb" (atat a experimentelor cat si a subiectilor)

• utilizarea metodelor probabilitatiimetodelor probabilitatii (statisticestatistice) in analiza si interpretarea rezultatelor

• 3.Evaluarea si Probabilitatea(4)– Probabilitatea (1)Probabilitatea (1) este o masura a

nesiguranteinesigurantei sau a variabilitatiivariabilitatii caracteristicilor intre diversii indivizi ai unei populatii:

• daca se va observa intreagaintreaga populatie, calcularea frecventelor relative ale variabilelor ofera toate informatiile referitoare la variabilitate

• 3.Evaluarea si Probabilitatea(5)– Probabilitatea (2)Probabilitatea (2)

• daca se va observa doar un esantionun esantion de indivizi din acea populatie, deductia de la esantion la populatie (de la specific la general) va implica identificarea:

– probabilitatilorprobabilitatilor evenimentelor observate – precum si a legilor probabilitatiilegilor probabilitatii care ne permit sa masuram nivelul de

nesiguranta al deductiilor noastre

• 4.Ipoteza(1)

– 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

• 4.Ipoteza(2)

– unul dintre instrumentele cele mai utile ale cercetarii medicale

este generarea ipotezelorgenerarea ipotezelor care, cand sunt testate vor conduce

la identificarea celor mai probabile cauzecelor mai probabile cauze de boala sau de

transformari in fenomenul observat

• 4.Ipoteza(3)– desi NUNU putem trage concluzii definitive sau sa

pretindem ca avem dovezi bazandu-ne pe metoda

inductiva, totusi ne putem apropia si mai mult de

"adevar" prin eliminarea ipotezelor existente si

inlocuirea lor cu unele avand o plauzibilitate si mai

• 4.Ipoteza(4)

– in cercetarea medicala, ipotezeleipotezele sunt adesea

construiteconstruite si testatetestate pentru a identificaidentifica niste cauzecauze

ale unor boli si a explicaexplica distributia bolilor in populatii

• 4.Ipoteza(5)

– in formularea ipotezelor legate de asociere si cauzalitate se

utilizeaza adesea canoanele gandirii inductivecanoanele gandirii inductive formulate de

MillMill

– Pe scurt aceste metode includ:

• metoda diferentelor

• metoda punerii de acord ("agreement")

• metoda variatiei concomitente, sau efectul doza-raspuns

• metoda analogiei

• 4.Ipoteza(6)– metoda diferentelordiferentelor – cand frecventa unei boli este foarte

diferita in doua circumstante diferite, iar un factor poate fi identificat intr-o circumstanta si NUNU in cealalta, acest factor sau absenta lui poate fi cauza bolii

• ex: diferenta in frecventa cancerului pulmonar la fumatori si nefumatori

• 4.Ipoteza(7)– metoda punerii de acordpunerii de acord ("agreement") – daca un

factor, sau absenta lui este comuna unui numar de circumstante diferite care se constata ca sunt asociate cu prezenta unei boli, acel factor, sau absenta lui poate fi asociata cauzal cu boala

• ex: aparitia hepatitei A este asociata cu venirea in contact cu un pacient, cu aglomeratia si cu igiena deficitara, fiecare contribuind la transmiterea virusului hepatitic

• 4.Ipoteza(8)– metoda variatiei concomitentevariatiei concomitente, sau efectul doza-efectul doza-

raspunsraspuns• exemple de variatie concomitenta:

– cresterea expresiei gusei endemice paralel cu scaderea nivelului iodului in dieta (alimentatie)

– cresterea frecventei leucemiei odata cu marirea expunerii la radiatii

– cresterea prevalentei elefantiazisului in ariile cu o crestere a endemicitatii filariei

• 4.Ipoteza (9)– metoda analogieianalogiei – distributia si frecventa

unei afectiuni sau a unui efect pot fi suficient de similare cu acelea ale unei alte boli incat sa sugereze o cauza comuna

• ex: infectia cu virus hepatitic B si neoplasmul hepatic

Corin Badiu, 2011

Metodologia cercetMetodologia cercetăării rii şştiintiinţţificeifice

Ipoteza de lucruOrganizarea studiului

Tipuri de studii

Obiective

• Construire unui mod de documentare, emitere de ipoteze si testarea acestora

• Dobandirea abilitatilor de cercetare

• Redactarea unui protocol de 10 pagini pentru un studiu real / ipotetic

• 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 interventional)

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 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

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 aptitudinile 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– Modifica intrebarea / designul

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 Factori care influenteaza conceptia studiuluistudiului

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/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

Relevant

Sapte 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– Caz control– Cohorta

1. Studii Experimental / Interventionale -

Randomized controlled trial (RCT)

• Evaluarea de noi metode de profilaxie si tratament– Medicamente si terapii noi pentru boli– Tehnologii medicale si tehnici de ingrijire noi– Metode noi de preventie primara– Programe noi de screening si detectare precoce– Sisteme noi de asistenta sanitara comunitara

(community trial )– Impactul noilor politici in sistemul de sanatate si

finantarea sistemului sanitar ( 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

Elemente Design

Randomizare

Tratament nouTratament curent

/no treatment

Definirea populatiei

AmelioratNe

ameliorat Ameliorat

Interventie

Outcome

Selectia subiectilor - trasaturi similare - criterii includere /excludere

Alocarea subiectilor

Colectarea datelor

Masking (blinding)

Ne ameliorat

• 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.

Randomized Controlled Trial

Types of RCT:• Superiority or equivalence trials A

• Parallel - most common B

• Cross over- Planned –washout

period

B A- Unplanned

Surgical Medical randomized

randomized

Refuse surgery Require surgery

Analyze outcome by intention to RxNo surgerySurgery

Limite

1. ? Eficienta în comunitati necontrolate

2. Refuzul consimțământului informat - selectare automată(persoane care participă sunt diferite de cele care nu o fac)

3. Necomplianta (persoanele compliante sunt foarte diferite de cele care nu sunt)- Drop-out: nu adera la regim experimental, pierderea din studiu- Drop-in: nu adera la regimul de control

4. Complianta- necesita monitorizare

5. Cele mai costisitoare tipuri de studii

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?

• Atunci când există dovezi bune pentru asocierea bolii, cu o anumită expunere

• Atunci când expunerea este rară și incidența bolii in randul celor expusi este frecventă

• Când intervalul de timp dintre expunere si boala este scurt

• Atunci când cercetătorul are o speranță de viață lungă!

Cohorta

• Cohorta: "orice grup desemnat de persoane care sunt urmărite pe o perioadă de timp“

• Cazurile selectate in cohorta trebuie sa fie fara boala cercetata la începutul urmaririi (populația la risc)

• De obicei cohorta este definita sau subîmpărțita în funcție de statutul de expunere

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

–Control mai bun al calității și cantității de date

–Potențial mai mic de bias–Mai consumatoare de timp–Mai scumpe

Retrospective

–Control mai slab al calității și cantității de date

–Potențial mai mare de eroare

–Mai rapide–Mai ieftine

Pierderea din urmarire(Loss to Follow-up)

• Problemă, mai ales dacă subiecții pierduti sunt la risc mai mare / mai mic de a dezvolta boala comparativ cu alti subiecti

• Chiar mai rău dacă “lost to FU” apare diferit in subgrupuri Un nivel <60% de urmarire in cohorta este, în general, privit cu scepticism

Analiza datelor – studii de cohorta

Start with exposure, then follow to see whether

Disease +

Exposed +

Exposed -

Disease - total Incidence rate of disease

• Riscul absolut = incidența cazurilor de boală în lotul expus / populația totală

Riscului relativ =

Taria asociatiei (Odds Ratio) = ad / bc

Analiza datelor – studii de cohorta

Incidenta bolii la E+Incidenta bolii la E-

Limite

• Unele expuneri la risc se pot modifica în timp ex îmbătrânire, stilul de viață (dietă, fumat), expunerea la produse farmaceutice, poluarea aeruluiModificări privind metoda de-a lungul timpului, identificarea bolii Prospectiv - follow-up, deci cu perioade lungiCostisitor

•Potential de eroare:

eroare de selecție (care subiect a fost expus și care nu)eroare de anamneza - date istoriceeroare în evaluarea rezultateloreroare prin lipsa de răspuns și pierdere la f / ueroare analitică

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

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

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

Proportion of exposed

a/a+c b/b+d

• 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

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

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

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)

Corin Badiu, 2007

Colectarea datelor

Strategii de masurare

Obiective

• Stabilirea tipurilor de variabile– Surse IT de date– Identifica si localizeaza seturile corecte de date

• In institutie• In afara institutiei

• Strategii de masurare

• Analiza, interpretarea si raportarea rezultatelor– Selecteaza programul adecvat: Excel, SPSS– Foloseste programele pentru analize statistice simple

si prezentarea grafica a rezultatelor– Interpreteazarezultatele

Predictor* Rezultat

Variabile de confuzie*

Modificatori ai efectului*

Tipuri de variabile

*Considerate general ca expunere la factori de risc

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

Studii clinice

Descriptive Analitice

Experimentale Observationale

Cohorta Caz-control Cross-sectional

Variabila predictor(independenta)

Variabila rezultat (dependenta)

Variabile

Evidence Based Medicine

• Metode de tratament sustinute de dovezi clinice si de cercetare.

• Necesita integrarea celor mai bune dovezi din cercetare pentru diagnostic si tratament cu experienta clinica.

• Ia in considerare ce este optim pentru fiecare pacient precum si preferintele acestuia.

Realitatea

• Cercetarea asupra eficientei de tratament face subiectul unui numar mic de articole.

• Evidence based medicine este considerat un concept ce foloseste baze de date inclusiv studii sistematice de caz pentru a ghida interventii terapeutice.

• Dovezile trebuie evaluate intr-un context terapeutic efectiv, “Ce tip de interventie capata sens pentru mine ca practician?”

Clinical Questions

• What is the best choice of therapy for my patient?

• Is this program theoretically sound?

• Does this therapy program work?

• How long with the therapy take?

• Where do I go from here?

Practicing Clinicians Needed!

Clinicians

– are on the front line

– have necessary clinical expertise

– know their patients well

– are naturally scientific thinkers

– are well-versed in data collection

– know how to look for outcomes

Baseline Measurements

• A baseline is a measure of response rates in the absence of treatment

• Baselines

– Establish a need for treatment

– Document improvement

– Allow us to modify if we don’t see improvement

Baseline Data

• Create a set of exemplars of each of your targets and prepare a recording sheet.

• Utilize criterion referenced measures.

Data Collection Strategies

• Always have more than one measurement• Check the reliability of the baseline data• Select research/clinical design

Research/Clinical Designs

• ABA designs– Test, treat and test

• ABAB designs– Test, treat, test and treat

• Time-Series designs– Establish stable baseline– Begin treatment– Measure treatment results

• Multiple-Baseline designs– Have a number of different baselines– Each baseline must be independent of the others– Only treat one variable

Data Collection Instruments

Requirements

• Reliable

• Valid

• Responsive

• Universal

• Unbiased

Data Collection Instrument

Is it reliable?Will the instrument measure consistently across:• Different testing situations?

Test-retest reliability

• Different judges?Inter-rater reliability

Is it valid?

• Is the instrument being used to measure the kind of data for which it was intended?

Is it responsive?• The instrument should be equally sensitive, whether a

characteristic is present or absent.

Must measure both:• False-negatives:

You thought it was intact, but it was torn.• False-positives:

You thought it was torn, but it was intact.

Is it universal? The investigator should

employ a widely used data collection instrument, which helps minimize reporting bias because the data can then be compared with other published literature.

• There should be no difference between the true value and the value that an investigator actually obtains– other than a difference caused by sampling variability.

Is it unbiased?

Sampling Methods

• Random Sampling (Simple)

• Systematic Sampling

• Stratified Sampling

4. Cluster Sampling

5. Convenience Sampling

6. More complex sampling

Qualitative and Quantitative Variables

Examples of qualitative variables are occupation, sex, marital status, and etc

Variables that yield observations that can be measured are considered to be quantitative variables. Examples of quantitative variables are weight, height, and age Quantitative variables can further be classified as discrete or continuous

Variables types

1. Categorical variables (e.g., Sex, Marital Status, income category)

2. Continuous variables (e.g., Age, income, weight, height, time to achieve an outcome)

3. Discrete variables (e.g.,Number of Children in a family)

4. Binary or Dichotomous variables (e.g., response to all Yes or No type of questions)

Scale of Data

1. Nominal: These data do not represent an amount or quantity (e.g., Marital Status, Sex)

2. Ordinal: These data represent an ordered series of relationship (e.g., level of education)

3. Interval: These data is measured on an interval scale having equal units but an arbitrary zero point. (e.g.: Temperature in Fahrenheit)

4. Interval Ratio: Variable such as weight for which we can compare meaningfully one weight versus another (say, 100 Kg is twice 50 Kg)

Variables in the protocol

• TYPES OF VARIABLE– independent

– dependent

– intermediate

– confounding

Independent Variable

• The characteristic being observed and/or measured that is hypothesized to influence an event or outcome (dependent variable).

• NOTE– The independent variable is not influenced

by the event or outcome, but may cause it or contribute to its variation.

Dependent Variable

• A variable whose value is dependent on the effect of other variables (ie., “independent variables”) in the relationship being studied. Synonyms: outcome or response variable.

• NOTE– an event or outcome whose variation we

seek to explain or account for by the influence of independent variables.

Intermediate Variable

• A variable that occurs in a causal pathway from an independent to a dependent variable. Synonyms: intervening, mediating

• NOTES– it produces variation in the dependent

variable, and is caused to vary by the independent variable.

– such a variable is “associated” with both the dependent and independent variables.

Confounding Variable

• A factor (that is itself a determinant of the outcome), that distorts the apparent effect of a study variable on the outcome.

• NOTE– such a factor may be unequally distributed

among the exposed and the unexposed, and thereby influence the apparent magnitude and even the direction of the effect.

Organizing Data

1. Frequency Table 2. Frequency Histogram 3. Relative Frequency Histogram4. Frequency polygon5. Relative Frequency polygon6. Bar chart7. Pie chart 8. stem-and-leaf display9. Box Plot

Frequency Table

Suppose we are interested in studying the number of children in the families living in a community. The following data has been collected based on a random sample of n = 30 families from the community.

2, 2, 5, 3, 0, 1, 3, 2, 3, 4, 1, 3, 4, 5, 7, 3, 2, 4, 1, 0, 5, 8, 6, 5, 4 , 2, 4, 4, 7, 6

Organize this data in a Frequency Table!

X=No. of Children Count

(Freq.)

Relative Freq.

0 2 2/30=0.067

1 3 3/30=0.100

2 5 5/30=0.167

3 5 5/30=0.167

4 6 6/30=0.200

5 4 4/30=0.133

6 2 2/30=0.067

7 2 2/30=0.067

8 1 1/30=0.033

Frequency Table

0 1 2 3 4 5 6 7 8

Frequency plot

Now suppose we need to construct a similar frequency table for the age of patients with Heart related problems in a clinic.

The following data has been collected based on a random sample of n = 30 patients who went to the emergency room of the clinic for Heart related problems.

The measurements are: 42, 38, 51, 53, 40, 68, 62, 36, 32, 45, 51, 67, 53, 59, 47, 63, 52, 64, 61, 43, 56, 58, 66, 54, 56, 52, 40, 55, 72, 69.

Frequency Table

Age Groups Frequency Relative Frequency

32 -36.99 2 2/30=0.067

37- 41.99 3 3/30=0.100

42-46.99 4 4/30=0.134

47-51.99 3 3/30=0.100

52-56.99 8 8/30=0.267

57-61.99 3 3/30=0.100

62-66.99 4 4/30=0.134

67-72 3 3/30=0.100

Total n=30 1.00

Frequency Table

Measures of Central Tendency

Where is the heart of distribution?

1. Mean 2. Median

3. Mode

Empirical Rule

For a Normal distribution approximately, a) 68% of the measurements fall within one standard

deviation around the mean

b) 95% of the measurements fall within two standard deviations around the mean

c) 99.7% of the measurements fall within three standard deviations around the mean

Prerequisite Skills

• Fundamental concepts of measurement• Scales of measurement• Distribution, central tendency, variability,

probability• Disease prevalence and incidence• Disease outcomes (eg, fatality rates)• Associations (correlation or covariance)• Health impact (eg, risk differences and ratios)• Sensitivity, specificity, predictive values

Scales of Measure

• Nominal – qualitative classification of equal value: gender, race, color, city

• Ordinal - qualitative classification which can be rank ordered: socioeconomic status of families

• Interval - Numerical or quantitative data: can be rank ordered and sizes compared : temperature

• Ratio - interval data with absolute zero value: time or space

Distribution, Central Tendency…

…Variability, Probability…

• Mean

• Median

• Mode

• Standard deviation

• Statistical Significance p < .01

Confidence Interval

Statistical SignificanceType I and Type II errors

Ho True Ho False

Reject Ho Type I errorCorrect decision

Do Not Reject Ho

Correct decision

Type II error

Null Hypothesis = Ho

Statistics Online Textbook

• The Statistics Homepage

• http://www.statsoftinc.com/textbook/stathome.html

Disease Prevalence and Incidence

• Prevalence– probability of disease in entire population at

any point in time– 2% of the population has diabetes

• Incidence– probability that patient without disease

develops disease during interval– 0.2% or 2 per 1000 new cases per year

Sensitivity, Specificity

• sensitivity = a / (a+c)

• specificity = d / (b+d)

Patients with disease

Patients without disease

Test is positive a bTest is negative

Predictive Value

• Positive predictive value = a / ( a+b)

• Negative predictive value = d / (c+d)

• Post-test probability of disease given positive test = a / (a+b)

• Post-test probability of disease given negative test = c / (c+d)

Patients with disease

Patients without disease

Test is positive a bTest is negative c d

Good Resource Sen, Spc, PV

• An Introduction to Information Mastery

• http://www.poems.msu.edu/InfoMastery/default.htm – Diagnosis

• Sensitivity and specificity• Predictive values• Likelihood ratios

• InfoRetriever – Calculators: Epidemiology, Diagnostic test

Bias in Clinical Trials

Areas in which bias can occur

Systematic error in . . .

• Allocation

• Response

• Assessment

Allocation or Susceptibility Bias

• Can occur when patient assignments to a trial group are influenced by an investigator’s knowledge of the treatment to be received.

• Can result in treatment groupsthat have different prognoses.

Allocation or Susceptibility Bias

• Treatment groups must have similar prognoses, which is achieved by:– Randomization of patients– Prospective evaluation of patients– Well-defined inclusion and exclusion criteria

Randomization in Clinical Trials

Occurs when patients are assigned to treatments by means of a mechanism that prevents both the patients and the investigator from knowing which treatment is being assigned.

Benefits of Randomization

• Prevents the systematic introduction of bias.

• Minimizes the possibility of allocation bias.

• Balances prognostic factors for treatment groups.

• Improves the validity of statistical tests used to

compare treatments.

Response & Assessment/Recording Bias

• Can occur when a patient reports a treatment response or when an investigator assesses that response—either person can be influenced by knowing the treatment.

• A patient or an investigator may have a preconceived idea of which treatment is better. The patient may also want to please the investigator.

Blinding

To minimize Response & Assessment/Recording Bias

• Single Blind (patient blinded): protects against response bias.

• Double Blind (patient and investigator blinded): protects against assessment/recording bias as well as response bias.

• Transfer bias– Occurs when patients are lost to follow-up.– Must be minimized.

• Performance bias– Can occur with a single surgeon or with

multiple surgeons.

Confounding Example

• Relationship between coffee and pancreatic cancer, BUT

• Smoking is a known risk factor for pancreatic cancer

• Smoking is associated with coffee drinking but it is not a result of coffee drinking.

What is confounding?

• If an association is observed between coffee drinking and pancreatic cancer– Coffee actually causes pancreatic cancer, or– The coffee drinking and pancreatic cancer

association is the result of confounding by cigarette smoking.

How to handle confounding

• If you know something is a possible confounder, in the data analysis use– Stratification, or– Adjustment

• Fear the unknown!

Study Design Taxonomy

• Treatment vs. Observational

• Prospective vs. Retrospective

• Longitudinal vs. Cross-sectional

• Randomized vs. Non-Randomized

• Blinded/Masked or Not– Single-blind, Double blind, Unblinded

Randomization: Definition

• Random Allocation– known chance receiving a treatment– cannot predict the treatment to be given

• Eliminate Selection Bias

• Similar Treatment Groups

ONE Factor is Different

• Randomization tries to ensure that ONE factor is different between two or more groups.

• Observe the Consequences

• Attribute Causality

Types of Randomization

• Standard ways:– Random number tables (see text)– Computer programs

• NOT legitimate– Birth date– Last digit of the medical record number– Odd/even room number

Types of Randomization

• Simple

• Blocked Randomization

• Stratified Randomization

Simple Randomization

• Randomize each patient to a treatment with a known probability– Corresponds to flipping a coin

• Could have imbalance in # / group or trends in group assignment

• Could have different distributions of a trait like gender in the two arms

Block Randomization

• Insure the # of patients assigned to each treatment is not far out of balance

• Variable block size– An additional layer of blindness

• Different distributions of a trait like gender in the two arms possible

Stratified Randomization

• A priori certain factors likely important (e.g. Age, Gender)

• Randomize so different levels of the factor are balanced between treatment groups

• Cannot evaluate the stratification variable

Stratified Randomization

• For each subgroup or strata perform a separate block randomization

• Common strata– Clinical center, Age, Gender

• Stratification MUST be taken into account in the data analysis!

Outline

• Introductory Statistical Definitions

• What is Randomization?

• Randomized Study Design

• Experimental vs. Observational

• Non-Randomized Study Design

• Stat Software, Books, Articles

Types of Randomized Studies

• Parallel Group

• Sequential Trials

• Group Sequential trials

• Cross-over

• Factorial Designs

Parallel Group

• Randomize patients to one of k treatments

• Response– Measure at end of study– Delta or % change from baseline– Repeated measures– Function of multiple measures

Ideal Study - Gold Standard

• Double blind

• Randomized

• Parallel groups

Example taken from Statistics: The Art and Science of Learning from Data

Two Scenarios

• Study 1– A U.S. study (2000) compared 469 patients with brain cancer

to 422 patients who did not have brain cancer. The patients’ cell phone use was measured using a questionnaire. The two groups’ use of cell phones was similar.

• Study 2– An Australian study (1997) conducted a study with 200

transgenic mice. One hundred were exposed for two 30 minute periods a day to the same kind of microwaves with roughly the same power as the kind transmitted from a cell phone. The other 100 mice were not exposed. After 18 months, the brain tumor rate for the exposed mice was twice as high as that for the unexposed mice.

Questions to Consider

• How do the two studies differ?– Study 1

– Study 2

• Why do the results of different medical studies sometimes disagree?

• Could the second study be performed on human beings?

• Suppose a friend recently diagnosed with brain cancer was a frequent cell phone user. Is this strong evidence that frequent cell phone use increases the likelihood of getting brain cancer?– Informal observations of this type are called

_____________ _____________.– You should rely on reputable research studies,

not anecdotes.

Two Main Ways to Gather Data

• Observational Study– The researcher observes values of the response and

explanatory variables for the sampled subjects without imposing any treatments

– Example: • Experiment

– The researcher assigns experimental conditions (also called treatments) to subjects (also called experimental units) and then observes outcomes on the response variable.

– Treatments correspond to values of the explanatory variable

– Example:

Types of Observational Studies

• Retrospective– Observational studies that look back in time

• This is sometimes done to find risk factors for certain diseases

• Cross-Sectional– Observational studies that take a cross

section of the population at the current time

• Prospective– Observational studies in which subjects are

followed into the future

Advantages of Experiments over Observational Studies

• In an observational study, there can always be lurking variables affecting the results.

• This means that observational studies can _________ show causation.

• It is easier to adjust for lurking variables in an experiment.

• In general, we can study the effect of an explanatory variable on a response variable more accurately with an experiment than with an observational study.

Disadvantages of Experiments

• They can be ____________ to perform on the subjects in which you are interested.

• It can be difficult to monitor subjects to ensure that they are doing what they are told.

• They can take many years, even decades, to complete.

• Results of experiments that use animals do not ______________ to humans.

• They are unnecessary the question of interest does not involve trying to assess _____________.

Sampling Designs for Observational Studies

• Simple Random Sampling (SRS)– A simple random sample of n subjects from a population is one in

which each possible sample of that size has the _______ chance of being selected.

• Stratified Sampling– A stratified random sample divides the population into separate

groups, called ________, and then selects an SRS from each stratum.

• Cluster Sampling– A cluster random sample can be used if the target population naturally

divides into groups, each of which is representative of the entire target population. In this method, a SRS of groups (or strata) is taken. Every member of the selected groups is put into the sample.

• Systematic Sampling– A systematic sample selects every kth person

from the sample frame. The researcher randomly selects a number between 1 and k in order to know which person to select first, then selects every kth person after this.

Advantages of the Various Sampling Designs

• Simple Random Sampling (SRS)– It is the easiest most widespread form of sampling.– Each subject has an _______ chance to be in the

sample.– The sample enables us to determine how likely it is

that descriptive statistics (like the sample mean) fall close to corresponding values for which we would like to make inference (like the population mean).

Advantages of the Various Sampling Designs

• Stratified Sampling– It ensures that there are enough _________ in

each group that you want to compare.

• Cluster Sampling– It does not require a sampling frame of subjects.– It is less ___________ to implement.

Bias in Sampling

• A sampling method is _________ if– The sample tends to favor some parts of the

population over others.– In other words, the results from the sample are not

representative of the population.

• Obviously, __________ samples are our goal.

Types of Bias

• Undercoverage– Occurs when a sampling frame leaves out some groups in the

population

• Nonresponse bias– Occurs when some sampled subjects cannot be reached, refuse to

participate or fail to answer some questions

• Response bias– Occurs when the subject gives an incorrect response or when the

question wording or the way the interviewer asks the questions is confusing or misleading

Examples of Poor Samples that Result in Bias

• Convenience Samples

• Voluntary Response Samples

Elements of a Good Experiment

• Control group– Gives us something to compare against– Enables us to control the __________ _______

• The placebo effect occurs when patients seem to improve regardless of the treatment they receive.

• Randomization– Eliminates ______ that can result when researchers assign

treatments to the subjects– Balances the group on variables that you know affect the

response– Balances the group on _________ variables that may be

unknown to you

Elements of a Good Experiment

• Blinding– Increases reliability of the results

• _________-blind: subjects do not know the treatment assignment

• _________-blind: neither the subjects nor those in contact with the subjects know the treatment assignment

Example

• A pharmaceutical company has developed a new drug for treating high blood pressure. To determine the effectiveness of the drug, the company conducted an experiment in which subjects with a history of high blood pressure were treated with the new drug.

• A later experiment randomly divided subjects with a history of high blood pressure into two groups. Group A was treated with the new drug as before. Group B received the most popular drug on the market at that time. The subjects were unaware of which treatment they received. 60% of the patients in Group A improved, while 63% of the patients in Group B improved.

• The __________ experiment is better because

Example taken from Statistics: The Art and Science of Learning from Data

Example• To investigate whether antidepressants help smokers to quit smoking, one

study used 429 men and women who were 18 or older and had smoked 15 cigarettes or more per day in the previous year. They were all highly motivated to quit and in good health. They were assigned to one of two groups: one group took an antidepressant called Zyban, while the other group did not take anything. At the end of a year, the study observed whether each subject had successfully abstained from smoking.

Logic Behind Randomized Comparative Experiments

• Randomization ensures that the groups of subjects are similar in all respects before the treatments are applied.

• Using a control group for comparison ensures that external influences operate equally on both groups.

• If the groups are large enough, natural differences in subjects will average out.

• This means that there be little difference in the results for the groups unless the treatments themselves actually cause the difference.

Did You Know?

• Observational studies can also have control groups.– These are called ______-________ studies.– The cases are people who have a certain disease or condition,

and the controls are people who do not have the disease.– Their purpose is to see if one of the explanatory variables is

related to the disease.– _________ from the beginning of these notes is an example of a

case-control study.

Important Points• Types of studies:

– Observational studies and experiments– Experiments control for lurking variables

• Sampling designs:– SRS, stratified random samples and cluster samples– SRS is the preferred method

• Potential sources of bias:– Undercoverage– Response bias– Nonresponse bias– Convenience sampling– Voluntary response sampling

• Elements of good experiments:– Control group, randomization and blinding

Important Points

• If a group is underrepresented in the sample, we cannot make inference about it.

• We must be careful when interpreting the results of observational studies.

• For comparison of several treatments to be valid, you must apply all treatments to similar groups of experimental units.

• Interesting questions are usually pretty tough to answer. This is due in part to the fact that no single experiment or observational study can determine causation.

Stop and Think!!!Stop and Think!!!

•Write the study!

•Describe & classify the variables.

•Instruments for measure?

•Bias?

•Prepare to analyze data!

Corin Badiu, 2007

Consimtamantul informat in cercetarea ştiinţifică

Etica Definitii academice si practice

• Ramura a disciplinelor filozofice, considerata stiinta de normare intrucat se ocupa de normele conduitei umane. [academic]

• Procesul prin care se aplica valorile morale la situatii actuale de viata. [practic]

Aspecte istorice si religioase• Etica: un corp de norme si standarde de conduita umana

care guverneaza comporetamentul indivizilor si grupurilor. [istoric]

• Etica: disciplina de viata rezultata din aplicarea normelor si preceptelor religioase [Religie]

Individ si Grupuri

• Etica: domeniu de studiu care ajuta individul pentru aplicarea propriilor valori si principii pentru a le conduce comportamentul. [individual]

• Etica: un set de reguli pe care le studiem si aplicam pentru a duce la indeplinire misiunea unei organizatii / institutii. [group]

Etica instututionala

• Institutie = grup:– Actioneaza colectiv pentru indeplinirea scopurilor

institutionale

• Institutie = individ:– Foloseste valori comune cu etica individuala pentru a

lua decizii

• Atat institutiile cat si indivizii:– Norme de etica

Protocolul de evaluare etica in cercetare

1. Fond, Scopuri, Obiective

2. Metodologia cercetarii

3. Participanti

4. Recrutare

5. Riscuri si Beneficii

6. Confidentialitate

7. Compensare

8. Conflict de Interese

9. Elaborarea si aplicarea consimtamantului Informat

10.Evaluarea prin comitete si institutii

11.Contract

12.Trialuri Clinice

13.Anexe

Fond, Scopuri, Obiective

Care este subiectul cercetarii?

Ce scopuri se vor indeplini prin cercetare?

Care sunt principalele intrebari la care se doreste raspuns?

Descrie pe scurt fondul stiintific al studiului

½ pagina

Metodologia cercetarii

Secventa logica de evenimente din cadrul studiului (protocol)

Cum se vor obtine datele?

Descriere detaliata pentru fiecare metoda. Pune urmatoarele intrebari:

Cat dureaza interviul/chestionarul/observatia experimentala?

Cand (in ce perioada) va avea loc?

Unde va avea loc?

Participantii vor avea posibilitatea sa intervina in chestionar/studiu? Daca da, ofera detalii.

Care sunt implicatiile /aplicatiile cercetarii?

Principii ale eticii in cercetare

• Onestitate• Obiectivitate• Integritate (cine esti, ce faci, ce spui)• Utilizarea eficienta a resurselor (timp, materiale,

echipamente, personal)• Colegialitate (utilizare in comun)• Recunoasterea autoritatii (ca authorship si

mentor)• Deschidere (dezvaluirea detaliilor)

Practica responsabilitatii cercetarii

• Ce inseamna?– Urmarirea si aplicarea unui protocol scris– Verificarea si documentarea datelor (inclusiv lotul

de reactivi, date de exp., etc.)– Pastrarea adecvata a rezultatelor si specimenelor– Pastrarea adecvata a reactivilor si chimicalelor– Mentinerea si calibrarea adecvata a

echipamentelor– Utilizarea Standardelor Procedurilor de Operare

(SOP)– Grija pentru animalele de experienta

Cine sunt participantii? Organizatii? Indivizi?

De ce au fost alesi pentru studiu? (criterii de excludere / includere)

Cati sunt?

Argumenteaza dimensiunea esantionului

Participanti

Cum veti obtine o lista a potentialilor participanti?

Sistem de contact

telefonic

scrisoare ?

Grupuri de studiu:

Control,

Recrutare

Nu exista risc minim anticipat.

Participantii vor fi informati despre natura studiului si modalitatii de participare, inclusiv asupra faptului ca se pot retrage oricand.

Participantii (si raspunsurile lor privind includerea in studiu) vor fi luate ca atare

Standarde de aplicare:

Riscuri si Beneficii

Cine va avea acces la date?

Se va inregistra interviul?

Cum va fi protejata identitatea participantilor? Se codifica toate datele?

Cum se stocheaza datele in timpul studiului?

Cand se distrug datele?

Cum se va pastra confidentalitatea ? Se va exclude orice informatie de identificare?

Confidentialitate

• Fundamental in cercetarea pe subiecti umani

• Este un proces si nu un formular.

• Formularul este doar documentul care atesta ca procesul de informare liber consimtita a avut loc.

Procesul de consimtamant informat

Se va obtine consimtamant informat scris?

De la nivel institutional?

De la decan/ rector?

Consimtamantul informat trebuie obtinut de la toti participantii

Pentru studii avand ca subiecti copii, consimtamantul scris al parintilor / tutorilor este obligatoriu

Interviu – consimtamant scris

Chestionare – Prin completarea chestionarelor

Cum obtinem CI?

• Variaza in functie de designul studiului si natura participarii

• Verbal vs. Scris• Investigator vs. Co-investigatori / asistenti

Text Telefonic / email

Exemple de scrisori de consimtamant

Ghiduri de Observatie clinica

Chestionare

Interviu sau intrebari de grup

Elementele procesului de consimtamant informat• Informatie orala si scrisa pe grade de instruire• Afirmatia explicita ca studiul implica cercetare,

cu descrierea procedurilor, duratei, identificarea procedurilor experimentale

• Riscuri si eventual discomfort anticipat• Beneficii anticipate pentru subiecti sau altii• Natura voluntara a participarii la studiu• Capacitatea de a se retrage oricand

• Enumerarea alternativelor• Afirmatie legata de confidentialitate / anonimat• Afirmatie legata de compensare / tratament

medical• Afirmatie legata de persoana de contact pentru

intrebari legate de drepturile subiectilor, protocolul de cercetare, riscuri asociate protocolului

Costuri

• Consimatamantul informat trebuie sa transmita clar explicatia costurilor pentru care subiectul este responsabil.

Evaluarea riscurilor participantilor

Raportarea evenimentelor adverse• Probleme neanticipate• Evenimente adverse serioase

Noi date pot duce la:• Reevaluarea riscului• Modificarea formularului de consimtamant• Terminarea prematura a protocolului de cercetare

Populatii vulnerabile

• Copii

• Prizonieri

• Indivizi cu retard mental

• Dementa/ Coma/ Starea vegetativa

• Boli mentale

• Gravide

• Pacienti in urgenta

Consimtamant deplin informat

o Liber de coercitiefara teama / exploatarea puterii / pozitiei

o Consimtamant oficialNu este tacit ci explicit, scris!

o Scopul si metodele studiului?o Ce se asteapta de la participanti?o Cum se colecteaza datele?o Participantii pot sa comenteze /

interpreteze datele ?o Se va publica cercetarea?o Care sunt beneficiile si rezervele in a fi

participant la studiu?

Respect pentru copii

• Consideratii legale: datoria de ingrijire

• Obtinerea consimtamantului informat de la copii

Managing Risks to Subjects

Adverse Event Reporting• Unanticipated problems• Serious adverse events• New dataMay lead to:• Reassessment of risk• Changes to consent form or reconsent• More frequent oversight by the IRB• Early termination of the protocol

Healthy volunteers

• Volunteers may not stand to benefit directly, but could ultimately contribute to development of a new therapy that the participant might then use.

• Require particularly close monitoring, because they can pose a risk to a volunteer's health or life.

Confidentiality

• Unless you guarantee confidentiality you probably won’t gain consent and you certainly won’t obtain significant data.

• Once you agree confidentiality then this must be honoured (BUT: our duty of trust / promise is outweighed by our obligation to prevent harm to others).

• Must ensure that confidentiality is not breached directly (gossiping) or by accident (leaving notes lying around).

Anonymity

• Confidentiality is best assured by anonymising collection of data.

• Anonymity is increasingly difficult as advances in technology are made

Respect for children

• Legal considerations: duty of care

• Gaining informed consent from children

• Empowerment: giving children a voice

Choice of control

• “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.” (Helsinki 2000)

• Balance the need to answer the valuable question in a scientifically rigorous way, while minimizing risks and maximizing benefits to participants.

Frequently Asked Questions

• 1. How long will my review take?• 2. Who can I contact to find out the status of my

review?• 3. Who can I contact for clarification of review

comments?• 4. When can I begin my research?

The Ethics Review Process

Research as burden or benefit?

Research as ‘burden’

Subjects need protection

Research as ‘benefit’

Subjects need access

Vulnerability

• There is an order of preference in selecting subjects, for instance, adults before children (Belmont Report)

• Exclude vulnerable subjects unless their participation is needed for scientific reasons (CIOMS)

Essential Elements of Ethical Research

Balance of Risks and Benefits

Non-maleficence and Beneficence

• Minimize risks to subjects• Maximize benefits to individual subjects and

to society• Benefits should be proportional to or outweigh

risks.

Risks in research

• Defining risks – Probability and magnitude– Types of risk– Uncertainty

• Minimizing risks

• Limiting risk

Benefits in research

• Defining benefits

– Direct versus secondary benefits

• Maximizing benefits

• Balancing risks and benefits

Benefits and Risks in Research

[I]nterests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects’ rights have been protected.

The Belmont Report

Independent Review

Minimize conflict of interest

Public Accountability

Independent review of clinical research ensures the public that investigator biases have not distorted the approach, that ethical requirements have been fulfilled, and that subjects will not be exploited.

Criteria for IRB Review (45CFR.46.111 and 21CFR56.111)

• Risks … are minimized.

• Risks are justified by anticipated benefits, if any, to the subjects or the importance of the knowledge to be gained

• Subjects will be selected and treated fairly

• Informed consent is adequate

Informed Consent

Respect for Persons

Voluntary agreement to participate, based on understanding the objectives, risks, benefits, and alternatives of the research.

Key points

• Integrity

• Fully informed consent

• Confidentiality

• Anonymity

• Respect for children

Respect for Enrolled Subjects

Beneficence and Respect for Persons

• Right to withdraw.• Confidentiality of subject data.• Informing subjects of new information and of

study results.• Monitoring subject welfare.

Balancing principles

• Example: Randomized Controlled Trials

• Balancing the need for a rigorous design with the obligation to maximize benefits and minimize harms– Equipoise– Randomization– Choice of control

Choice of control

• “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.” (Helsinki 2000)

• Balance the need to answer the valuable question in a scientifically rigorous way, while minimizing risks and maximizing benefits to participants.

Corin Badiu, 2011

Etica in cercetarea ştiinţifică

Consimtamantul informat

Etica Definitii academice si practice

• Ramura a disciplinelor filozofice, considerata stiinta de normare intrucat se ocupa de normele conduitei umane. [academic]

• Procesul prin care se aplica valorile morale la situatii actuale de viata. [practic]

1. Fond, Scopuri, Obiective

2. Metodologia cercetarii

3. Participanti

4. Recrutare

5. Riscuri si Beneficii

6. Confidentialitate

7. Compensare

8. Conflict de Interese

9. Elaborarea si aplicarea consimtamantului Informat

10.Evaluarea prin comitete si institutii

11.Contract

12.Trialuri Clinice

13.Anexe

Text Telefonic/email

Exemple de scrisori de consimtamant

Ghiduri de observatie clinica

Chestionare

Interviu sau intrebari de grup

Etica cercetarii clinice

• Cerintele etice in cercetarea clinica au ca scop:

– Limitarea posibilitatii de exploatare;

– Siguranta ca sunt respectate drepturile pacientilor in timp ce acestia ajuta la imbunatatirea cunoasterii.

Coduri etice si Ghiduri

• Codul Nuremberg (1949)

• Declaratia de la Helsinki (1964- 2000)

• Raportul Belmont (1979)

• Ghiduri Internationale OMS (1993, 2002)

• ICH/GCP-International Conference on Harmonization- Good Clinical Practice (1996)

Perspective istorice• Tribunalul de razboi de la Nuremberg (1947) –

judecarea a 23 medici si militari germani care au comis crime de razboi si crime impotriva umanitatii. Teste inadmisibile efectuate cu scop de cercetare pe mii de prizonieri din lagarele de concentrare, fara a obtine consimatamant informat.

• Tuskegee Syphilis Study (1932-1972) – Ca parte componenta a unui proiect de cercetare condus de serviciul public de sanatate din SUA asupra 600 de barbati de culoare, provenind din categorii sociale defavorizate, din care 400 erau infectati cu sifilis, au fost monitorizati timp de 40 ani. Consulturile medicale erau gratuite; totusi, participantii nu au fost informati asupra bolii. Chiar cand a aparut posibilitatea terapiei antibiotice cu penicillina in anii 1950, studiul a continuat pana in 1972, participantii neprimind tratament. In anumite cazuri, cand participantii erau diagnosticati ca avand sifilis de catre alti medici, cercetatorii au intervenit pentru a preveni tratamentul. Multi participanti au murit de sifilis in timpul studiului. Studiul a fost oprit in 1973 de catre Departamentul de Sanatate si Educatie din SUA doar dupa ce a fost mediatizat si a devenit un element politic.

Nuremberg, GermanyDecember 9, 1946 to August 20,

– Necesar acordul voluntar înainte de participare

– Responsabilitatea investigatorului de a obține consimțământul

– Informațiile obținute prin utilizarea subiecților umani nu ar putea fi obtinute prin niciun alt mod

Tuskegee Syphilis Study

Raportul BELMONT National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research

• Distinctie intre cercetarea clinica si asistenta medicala

Raportul Belmont

Stabileste principiile etice și liniile directoare pentru Protectia Subiectilor Umani in cercetare (aprilie 1979)

A stabilit trei principii de bază, care sunt piatra de temelie a reglementărilor care implică protecția subiectilor umani in cercetare

• Respect pentru pacient; pastrarea independentei pacientului• Cercetarea trebuie sa aduca beneficii starii de sanatate a

pacientului• Expunerea corecta a avantajelor si dezavantajelor

• Folosirea Talidomidei - Talidomida a fost folosita in anii 1950 pentru a combate disgravidia. In perioada utilizarii sale, nu s-a transmis gravidelor faptul ca medicamentul era in curs de investigare, in faza de testare pentru obtinerea autorizatiilor. Dupa ce multe femei din Europa, Canada, si U.S.A au fost tratate, s-a descoperita ca are efecte teratogene, determinand maformatii fetale severe. Talidomida a fost oprita de la comercializare imediat in intreaga lume. Din pacate, aproximativ 12.000 copii s-au nascut cu malformatii severe datorate talidomidei.

Perspective istorice

• Experimente de Iradiere(1940s – 1960s) – Oficiali din U.S.A au studiat efectele radiatiei prin experimente pe pacienti spitalizati, femei gravide, copii cu intarziere mentala, cadre militare sau puscariasi. Putini dintre participantii la experimente au dat consimtamant informat. Majoritatea nu stiau ca sunt expusi la materiale radioactive. Oficialii proiectului Manhattan au autorizat experimente din timpul razboiului pentru a stabilii standarde de sanatate si siguranta pentru sutele de muncitori din fabricile de armament atomic.

Perspective istorice

Eventimente Santinela

• Crime de razboi naziste

• Experimente de iradiere

• Tuskegee Syphilis study

Procesul de la Nuremberg (1948)

Declaratia de la Helsinki (1963)

Raportul Belmont (1977)

Raspunsul la aceste abuzuri in cercetare

• Atrocitatile naziste in al doilea razboi mondial au atras atentia asupra lipsei standardelor internationale in cercetarea cu subiecti umani si au dus la formularea Codului de la Nuremberg (1948).

• Dezastrul talidomidei a dus la adoptarea "Amendamentului Kefauver" (1962) din Actul asupra alimentelor, cosmeticelor si medicamentelor, solicitand fabricantilor de medicamente sa puna la dispozitia FDA normele de siguranta si eficacitate a produselor lor iar medicii au fost obligati sa obtina consimtamant informat de la pacientii care ar putea primi o medicatie in curs de investigare.

• Declaratia de la Helsinki a rezumat munca Asociatiei Medicale Mondiale in 1964 (reevaluata in 2000) construita pe codul de la Nuremberg si este baza Normelor de Buna Practica Clinica folosite azi.

• Actul National de Cercetare (1974) care a aparut ca urmare a raspunsului la Studiului Tuskegee sifilis, instaureaza necesitatea ca subiectii umani sa fie protejati si sa beneficieze de achizitiile cele mai recente in cercetare, fiind baza de pornire pentru Raportul Belmont.

Declaratia de la Helsinki(Asociatia Medicala Mondiala)

• Aduce principiile etice utilizate de către medici care efectuează cercetarea umană

• A afirmat autonomia individului

• Declaratie adoptata universal pentru a asigura drepturile și siguranta subiecților umani inclusi in cercetare clinica

http://www.wma.net/en/30publications/10policies/b3/index.html

Declaration of Helsinki

• World Medical Association, 1964.

• Ultima evaluare - 2008

• Cercetarea cu subiecți umani se justifică doar atunci când gradul de risc pentru subiecți nu depășește importanța cunoștințelor care urmează să fie dobândite. DH este baza pentru normele de buna practica clinica utilizate în prezent.

Declaratia de la Helsinki

Probleme abordate:• Cercetarea clinica ar trebui să se bazeze pe experimente de

laborator (in vitro) și animale (in vivo)• Protocoalele experimentale trebuie să fie revizuite de către un

comitet independent• Acordul de participare la cercetare in scris-consimțământul

informat• Cercetările efectuate de către persoane fizice calificate

medical / si stiintific• Riscurile și beneficiile studiului• Impactul / respectul asupra vieții private a persoanei• Publicarea rezultatelor cercetării

Institutii de reglementare etica in Romania

• Comisia nationala de etica

• Agentia nationala a medicamentului

• Ordin 1224/2004 pentru aprobarea Ghidului privind studiile de siguranta nonclinica necesare in vederea efectuarii studiilor clinice pentru evaluarea medicamentelor

• ORDIN 615 /2004 pentru aprobarea Reglementãrilor privind implementarea regulilor de buna practica în desfãşurarea studiilor clinice efectuate cu medicamente de uz uman

Fond, Scopuri, Obiective

Care este subiectul cercetarii?

Ce scopuri se vor indeplini prin cercetare?

Care sunt principalele intrebari la care se doreste raspuns?

Descrie pe scurt fondul stiintific al studiului

½ pagina

Metodologia cercetarii

Secventa logica de evenimente din cadrul studiului (protocol)

Cum se vor obtine datele?

Descriere detaliata pentru fiecare metoda. Pune urmatoarele intrebari:

Cat dureaza interviul/chestionarul/observatia experimentala?

Cand (in ce perioada) va avea loc?

Unde va avea loc?

Participantii vor avea posibilitatea sa intervina in chestionar/studiu? Daca da, ofera detalii.

Care sunt implicatiile /aplicatiile cercetarii?

• Ce inseamna?– Urmarirea si aplicarea unui protocol scris– Verificarea si documentarea datelor (inclusiv lotul

de reactivi, date de exp., etc.)– Pastrarea adecvata a rezultatelor si specimenelor– Pastrarea adecvata a reactivilor si chimicalelor– Mentinerea si calibrarea adecvata a

echipamentelor– Utilizarea Standardelor Procedurilor de Operare

(SOP)– Grija pentru animalele de experienta

Cine sunt participantii? Organizatii? Indivizi?

De ce au fost alesi pentru studiu? (criterii de excludere / includere)

Cati sunt?

Argumenteaza dimensiunea esantionului

Participanti

Cum veti obtine o lista a potentialilor participanti?

Sistem de contact

telefonic

scrisoare ?

Grupuri de studiu:

Control,

Recrutare

Nu exista risc minim anticipat.

Participantii vor fi informati despre natura studiului si modalitatii de participare, inclusiv asupra faptului ca se pot retrage oricand.

Participantii (si raspunsurile lor privind includerea in studiu) vor fi luate ca atare

Standarde de aplicare:

Riscuri si Beneficii

Cine va avea acces la date?

Se va inregistra interviul?

Cum va fi protejata identitatea participantilor? Se codifica toate datele?

Cum se stocheaza datele in timpul studiului?

Cand se distrug datele?

Cum se va pastra confidentalitatea ? Se va exclude orice informatie de identificare?

Confidentialitate

• Fundamental in cercetarea pe subiecti umani

• Este un proces si nu un formular.

• Formularul este doar documentul care atesta ca procesul de informare liber consimtita a avut loc.

Se va obtine consimtamant informat scris?

De la nivel institutional?

De la decan/ rector?

Consimtamantul informat trebuie obtinut de la toti participantii

Pentru studii avand ca subiecti copii, consimtamantul scris al parintilor / tutorilor este obligatoriu

Interviu – consimtamant scris

Chestionare – Prin completarea chestionarelor

Cum obtinem CI?

• Variaza in functie de designul studiului si natura participarii

• Verbal vs. Scris• Investigator vs. Co-investigatori / asistenti

Elementele procesului de consimtamant informat• Informatie orala si scrisa pe grade de instruire• Afirmatia explicita ca studiul implica cercetare,

cu descrierea procedurilor, duratei, identificarea procedurilor experimentale

• Riscuri si eventual discomfort anticipat• Beneficii anticipate pentru subiecti sau altii• Natura voluntara a participarii la studiu• Capacitatea de a se retrage oricand

• Enumerarea alternativelor• Afirmatie legata de confidentialitate / anonimat• Afirmatie legata de compensare / tratament

medical• Afirmatie legata de persoana de contact pentru

intrebari legate de drepturile subiectilor, protocolul de cercetare, riscuri asociate protocolului

Costuri

• Consimatamantul informat trebuie sa transmita clar explicatia costurilor pentru care subiectul este responsabil.

Evaluarea riscurilor participantilor

Raportarea evenimentelor adverse• Probleme neanticipate• Evenimente adverse serioase

Noi date pot duce la:• Reevaluarea riscului• Modificarea formularului de consimtamant• Terminarea prematura a protocolului de cercetare

Populatii vulnerabile

• Copii

• Prizonieri

• Indivizi cu retard mental

• Dementa/ Coma/ Starea vegetativa

• Boli mentale

• Gravide

• Pacienti in urgenta

o Liber de coercitiefara teama / exploatarea puterii / pozitiei

o Consimtamant oficialNu este tacit ci explicit, scris!

o Scopul si metodele studiului?o Ce se asteapta de la participanti?o Cum se colecteaza datele?o Participantii pot sa comenteze /

interpreteze datele ?o Se va publica cercetarea?o Care sunt beneficiile si rezervele in a fi

participant la studiu?

Respect pentru copii

• Consideratii legale: datoria de ingrijire

• Obtinerea consimtamantului informat de la copii (de la 6-8 ani)

Confidentialitate

• Fara garantarea confidențialitatii, nu se poate semna acordul de consimtamant.

• Odată ce sunteți de acord cu confidențialitatea, atunci acest lucru trebuie să fie onorat (DAR: este de datoria noastră sa prevenim efectele negative pentru alții).

• Trebuie să se asigure că nu este încălcata confidențialitatea în mod direct (bârfe) sau de accident (lăsând notite despre caz, bilete de iesire, foi de observatie).

Anonimitatea

• Confidentialitatea este asigurata prin codificarea anonima a colectiei de date.

• Anonimizarea este din ce in ce mai dificila, pe masura progresului tehnologic

Conflictul de Interese

• O situație în care considerente financiare sau de altă natură cu caracter personal pot influenta, sau poate fi percepută de către alții ca generatoare de eroare pentru judecata profesională.

Conflict de Interese

• Financiar– Actiuni la firma farmaceutica, consultant, speaker

• Non-financiare– Recunoaștere in domeniu, dorința de a avansa teoria

cuiva– Nu suntem în măsură să eliminam conflictele de

interes, dar există și alte opțiuni: reducerea, evitarea sau prezentarea explicita a acestora

Conflict de Interese in cercetarea clinica

• Imposibil de eliminat in totalitate

• Pot fi financiare, personale, individuale sau institutionale

• Astazi: focuseaza pe conflictul financiar

• Normele de etica obliga investigatorii sa fie atenti la toate tipurile de conflict de interese

• De obicei, rezultă din rolul dublu al unui cercetător

De exemplu, un profesor / cercetator care doreste să colecteze date de la proprii studenti, sau un alt tip de relație în care cercetătorul are un rol de evaluare în raport cu participanții

• Potențialii participanți pot simti o presiune de a participa ce rezultă din relația de putere dintre profesor / student și nu se simt foarte confortabil sa refuze participarea

Conflict de Interese

• Impactul asupra drepturilor și bunăstării persoanelor implicate in cercetare

• Existenta unor conflicte de interese poate duce la erori in metodologia studiului si pierderea încrederii publicului

• Impactul asupra integrității datelor depuse la autoritățile de reglementare și reviste

Digital Data Ethics

• Simple adjustments to the ENTIRE image are usually acceptable.

• Selectively manipulating one area of the image is questionable.

• Cropping an image is usually acceptable.

• If used, software filters must be noted in the figure caption.

• The more processing you ‘have’ to do, the more ethically problematic the manipulations become.

Tipuri de date

• Body temperature

• Body weight

• Room temperature, humidity

• Food/water use

• Animal behavior (e.g., sleeping, aggression)

• Assay data

Data Selection & Retention

• Be careful how you “pick and chose”• Be consistent with regard to “high background”,

“artifact”, “low confidence values”, and “noise” (versus signal)

• When reporting your data, disclose what you did: – Two obese rats were excluded because…

– The first three data points were excluded because…

Dilemmas with Gels & Digital Data

Gels, X-Rays, photos are considered DATA

Ale cui sunt datele?

• Angajati si studenti care prin activitatea curenta se leaga în orice mod de practica responsabilității in cercetare trebuie să fie atribuiti Clinicii.

• Schimburile de material de cercetare cu cercetători din afara trebuie să fie încadrate în acorduri scrise. Clinica poate fi compensată pentru astfel de schimburi.

• Ce inseamna?– Urmarirea si aplicarea unui protocol scris– Verificarea si documentarea datelor (inclusiv lotul de

reactivi, date de exp., etc.)– Pastrarea adecvata a rezultatelor si specimenelor– Pastrarea adecvata a reactivilor si chimicalelor– Mentinerea si calibrarea adecvata a echipamentelor– Utilizarea Standardelor Procedurilor de Operare (SOP)– Grija pentru animalele de experienta

Pastrarea datelor

• Caiet de laborator semnat si datat

• Scris LIZIBIL

• Fara pasta corectoare

• Se taie cu o linie, se semneaza si se dateaza.

• Fara Postit (sticky notes).

• Fara pagini albe.

Author Requirements*

Authorship credit should be based on: 1) substantial contributions to conception and design,

or acquisition of data, or analysis and interpretation of data; and

2) drafting the article or revising it critically for important intellectual content; and

3) final approval of the version to be published.

Authors should meet conditions 1, 2, and 3.

*Intl Comm of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication. November 2009. http://www.icmje.org/ethical_1author.html

Authorship

• Those credited with authorship should be able to take public responsibility for the research.

Authorship*

Acquisition of funding, collection of data, or general supervision of the research group, alone, does not justify authorship.

*Intl Comm of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication. November 2009.

Authorship

Decide up front who will work on the manuscript and what the order of authors will be.

(Not all people working on the project will meet authorship requirements).

Research Misconduct

• Fabrication (creating data)

• Falsification (changing data)

• Plagiarism (using another’s words or ideas without giving them credit). – This includes cutting and pasting from the

Internet.

Why is Misconduct “Bad”?

• It affects the integrity of science as a profession (which potentially adversely affects research funding)

• It is not collegial

• Propels further generation of “bad” data as the initial data foundation is “bad”

Misconduct Research

• Survey of 3247 researchers:– 28% admitted to poor record keeping– 16% admitted to changing the design, methodology, or

results of a study in response to pressure from their funding source

– 15% admitted to dropping observations/data points based on a gut feeling

– 10% admit to giving authorship to people who didn't earn it

ref: Martinson et al. Nature 2005;435:737-738

What to do if you suspect misconduct…

• Don’t assume you are “right”• Don’t accuse• Try to verify your suspicion (there may be an

acceptable reason for what is going on)• Ask yourself, “what is my motive for getting

involved?”

• Ask the advice of someone you trust

Issues in Animal Research

Your Guide:

• Guide for the Care and Use of Laboratory Animals – info about vet care, housing, pain control euthanasia, etc.(http://www.nap.edu/readingroom/books/labrats/)

Issues in Animal Research

• Have you attempted to REPLACE animals with another model?

• Have you REDUCED the number of animals to the minimum needed for statistical purposes?

• Have you REFINED your lab techniques so that animal pain and suffering are as low as possible?

• Is your protocol approved by the CCF Institutional Animal Care and Use Committee?

Identification

• Make sure your animals are clearly identifiable, whether singularly or in groups.

• Options include cage labels, neck labels, tattoo, microchip, etc.

Housing Your Animals

• Consider the animal species • Housing should consider size of animal,

temperature, bedding needs, food, clean water, light, noise, humidity, contact with other animals, air exchange, vibration, etc.

• Keep the cages clean, and the animals free from harm from other animals. (This includes avoiding crowding within a cage).

Avoiding Animal Stress

If possible, before starting your project, CONDITION your animals to their environment, procedures, and research personnel.

Pain/Suffering

• An animal with signs of pain or distress not predicted in the protocol, must have the pain or distress alleviated promptly.

• Alleviation of such pain or distress must take precedence over completing a project.

• If this is not possible the animal must be euthanized without delay.

Moral problem in clinical research

• The goal of clinical research is generation of useful knowledge about human health and illness

• Benefit to participants is not the purpose of research (although it does occur)

• People are the means to developing useful knowledge; and are thus at risk of exploitation

CONCLUZII

• Etica în cercetarea începe cu cererea de finanțare

• Se aplică tuturor celor implicați în procesul de cercetare

• Se încheie cu publicarea și consecintele (clinice si stiintifice) acesteia

mcs tot

Documents