1. Cohort study Clinical Trial

2.  هدف مطالعه مي ‌ تواند اندازه گيري رخدادها، تعيين ارتباط بين عوامل خطرزا و بيماري يا پيامد مورد نظر، تعيين وضعيت بيماري در يك جمعيت، يا مطالعه در باره علل ايجاد بيماري باشد.  قابليت انجام مطالعه شامل مواردي چون قابليت دسترسي به افراد مورد مطالعه، ابزار يا مواد مورد نياز براي انجام مطالعه، و يا نيروي انساني، زمان، و بودجه مورد نياز براي انجام مطالعه باشد.  اعتبار مطالعه نيز شامل اين نكته مي ‌ شود كه اعتبار يافته هاي مطالعه با توجّه به مقدورات و امكانات مطالعه تا چه حد براي ما با اهميّت است.

3.  براي به دست آوردن مدارك بيشتر براي رد يا قبول وجود ارتباط بين مواجهه و بيماري مورد نظر انجام مي ‌ شود.  واژه كوهورت ( همگروه ) يك واژه رومي براي دسته اي از سربازان بود كه دريك گروه رژه مي رفتند.  در اپیدمیولوژي، يك همگروه ( كوهورت ) به معني گروهي از افراد تحت مطالعه است كه در يك خصوصيت يا تجربه مشترك هستند و با گذشت زمان پيگيري مي شوند.  مثل کوهورت تولد، کوهورت شغلی کارگران یک کارخانه مواد شیمیایی، دانش ‌ آموزان يك كلاس، سربازان در جبهه، گيرندگان يك واكسن و... 3

4. انواع مطالعات مشاهده ای توصیفی گزارش مورد / موارد مطالعات اکولوژیک مطالعات مقطعی تحلیلی مورد شاهدی کوهورت مداخله ای کارآزمایی بالینی کار آزمایی میدانی / اجتماعی

5. follow-up period

6.  Cohort Study Key Point: ◦ Presence or absence of risk factor is determined before outcome occurs.

7. 7 Target Population Diseased Not Diseased Exposed Not Exposed مشخصات مطالعات همگروهی : الف ) هم ‌ گروهها ) مواجهه ‌ دار و غیر مواجهه ‌ دار ) قبل از ظهور بيماري مشخص مي ‌ شوند. ب ) سمت و جهت مطالعه از مواجهه به سوي بيماری مي ‌ باشد. ج ) گروههاي مورد مطالعه را در طي دوره زماني مشخص از نظر ظهور بیماری مورد بررسي و پيگيري (Follow) قرار مي ‌ دهيم. Diseased Not Diseased

8. 8 موارد كاربرد مطالعات هم ‌ گروهي : الف ) وقتي شواهد خوبي براي ارتباط بين مواجهه و بيماري وجود دارد ( بر اساس مطالعات مقطعی و مورد شاهدی قبلی ). ب ) وقتي مواجهه نادر بوده ولي بروز بيماري در مواجهه يافتگان بالاست. ج ) وقتي فرسايش ( ریزش ) همگروههای مورد بررسی حداقل باشد ( پيگيري مواجهه ‌ يافتگان آسان باشد ، همکاری خوب داشته باشند و...) د ) وقتي منابع مالي فراهم باشد.

9. 9 3 ـ تركيب مطالعات همگروهي آينده ‌ نگر و گذشته ‌ نگر : همگروهها از زمانهای قبل انتخاب مي شوند و از امروز مورد پيگيری قرار می گيرند مثل بررسي ضايعات ناشي از عوامل شيميائي تاكنون و بررسي ميزان مرگ در اثر آن در آينده انواع مطالعات هم ‌ گروهي : 1 ـ مطالعه هم ‌ گروهي آينده ‌ نگر (Prospective) ( يا جاری concurrent ) مطالعه از زمان حال شروع مي ‌ شود و در آينده ادامه مي ‌ يابد. 2 ـ مطالعه هم ‌ گروهي گذشته ‌ نگر (Retrospective) ( يا Historical cohort ) نتيجه حاصل از مواجهه قبل از شروع مطالعه اتفاق افتاده است. مثل مواجهات شيميائي جنگ

10. مواجههپي آمد مواجههپي آمد مواجههپي آمد زمان حال گذشته آینده

11. unexposed exposed

12. unexposed exposed Incidence among exposed Incidence among unexposed

13.  Identify group of ◦ exposed subjects ◦ unexposed subjects  Follow up for disease occurrence  Measure incidence of disease  Compare incidence between exposed and unexposed group

14. اجزاء يك مطالعه همگروهي : 1. انتخاب افراد مورد مطالعه 2. به دست آوردن داده ‌ ها در مورد وضعيت مواجهه افراد مورد مطالعه 3. انتخاب گروه مقايسه 4. پيگيري 5. تجزيه و تحليل نتايج تجزيه و تحليل نتایج : 1 ـ تعيين ميزان بروز بيماری در گروه مواجهه يافته و گروه بدون مواجهه 2 ـ سپس برآورد کردن خطر بيماری در اثر مواجهه ( یا عامل خطر ) : خطر نسبی (Relative Risk) يا RR خطر قابل انتساب (Attributable Risk) يا AR

15.  Define Population at Risk using inclusion criteria  Individuals with outcome of interest at time of screening and enrollment are not eligible for study  Sub-clinical presentation of diseases may be present challenges in defining the cohort

16.  An incidence rate in an exposed population to the rate that would have been observed in the same population, at the same time if it had not been exposed

17.  Measures of association ◦ Relative risk (ratio of proportions) ◦ Odds ratio

18.  Relation between oral contraceptive use and circulatory disease  Study design: ◦ Identify 23,000 users and 23,000 nonusers of oral contraceptives ◦ Follow and ascertain presence or absence of circulatory disease

19.  An epidemiologic design in which the incidence of a disease (or condition) is estimated and compared among exposed and unexposed individuals.

20. Cohort study designs evolved because of the need for information on the length of survival and the natural history of disease Clinical and public health interest

21.  Prospective cohort studies ◦ Chronic Disease Cohorts (20 th Century) ◦ Framingham study of cardiovascular disease, 1948 ◦ Japanese atomic bomb survivors, 1946 ◦ British physician study, 1950s ◦ Colorado Plateau uranium miners, 1950s  Retrospective cohort studies ◦ Aniline-dye occupational cohort, 1954

22. No. MenNo. WomenTotal Random Sample3,0743,4336,507 Respondents2,0242,4454,469 Volunteers312428740 Respondents free of CHD19752,4184,393 Volunteers free of CHD307427734 Total free of CHD2,2822,8455,127

23.  Measuring exposure is one of the fundamental activities of a cohort study  Exposure measurement must be comparable for all members of the cohort  Carefully defined in advance of study  Specific attention should be given to the accuracy and precision of proposed measurements ◦ Pilot studies often needed

24.  Valid means of determining exposure include: a.Questionnaires (e.g., age, smoking history) b.Laboratory tests (e.g., cholesterol, hemoglobin) c.Physical measurements (e.g., blood pressure, height) d.Special procedures (e.g., electrocardiogram, x-rays) a.Medical records

25.  Cohort Study ◦ Key Point: ◦ Presence or absence of risk factor is determined before outcome occurs.

26. 1. Internal controls With a one-sample (population-based) cohort, exposure is unknown until after the first period of observation Example: a.Select the cohort (such as all residents of a given neighborhood) b.All members of the cohort are then given first round questionnaires, and/or clinical examinations, and/or testing to determine exposure c.The cohort is then divided into exposure categories based on those results

27. 2. External controls -If everyone in a cohort is exposed (such as workers in an industry), a separate cohort as similar as possible to the exposed in terms of income, education, geography, and age should be sought Example: Workers in a neighboring but unexposed industry

28. 3. Known population rates -If a comparison group cannot be assembled, known population rates of outcomes may be acceptable under some circumstances, if they are adjusted for the variables of interest -For lung cancer, however, rates are based on the population and are not adjusted for smoking -They are not, therefore, instructive to compare to populations with high smoking rates, such as miners

29.  Primary outcome - the main event that will be related to the exposure ◦ Failure-time outcomes  Death  Disease occurrence ◦ Repeated measures  Secondary outcomes - other events that are of interest and may corroborate the findings of the main outcome

30.  Completeness and non-participation ◦ 90% rule of thumb  All subjects must have an equal likelihood for detecting the outcome  Disease ascertainment must be comparable between the exposed and unexposed subjects ◦ Number of visits ◦ Reasons for additional evaluations  Follow-up mechanisms ◦ Active ◦ Passive

31.  Passive Surveillance ◦ Hospitals ◦ Disease Registries ◦ Clinics or physician offices ◦ Surveillance systems, e.g., National Death Index, CDC reportable conditions  Active surveillance ◦ Systematic evaluations for outcome of interest ◦ Regular time intervals ◦ In all study subjects

32.  Fixed Cohort ◦ A group of individuals recruited and enrolled at a uniform point in the natural history of a disease or by some defining event ◦ Cohort does not take on new members after it is assembled ◦ Examples  Patients admitted to the ER with acute MI  Survivors of Hiroshima bombings  Children born to HIV-infected mothers

33.  Open cohort ◦ A group of individuals recruited and enrolled through a mechanism that allows for in and out migration of people ◦ Defined by characteristic other than disease, e.g., geographic location, administrative unit ◦ Dynamic population ◦ Examples  Framingham Study

34.  Fixed Cohort Exposure (+) (-) x x x X = outcome

35.  Dynamic Exposure (+) (-) Years X X X X X = outcome

36.  اسامی مختلف : مطالعات مداخله ای = تجربی =Interventional=Experimental  مشابه مطالعه هم ‌ گروهي است ولي مداخله به دست پژوهشگر انجام مي ‌ شود.  توجه به مسائل اخلاقي در اين نوع پژوهش مهم است مواجهه exposure پیامد outcome

37.  This is a study where people are randomly allocated to receive (or not receive) a particular intervention (this could be two different treatments or one treatment and a placebo). This is the best type of study design to determine whether a treatment is effective.

38. Research Study Design DECISION: Alter the events under study? no yes Design Examples observational- case series - cross-sectional - case-control - cohort experimental- RCT - basic science

39. کاربردهای مطالعات تجربي : الف ) بررسی عوامل علیتی ( يا خطر ) بيماريها ب ) بررسی اثربخشي و كارائي خدمات بهداشتي و درماني ( دارو...)

40. Bias هاي مطالعات تجربي : 1 ـ Bias اطلاع افراد مورد مطالعه از نوع مداخله در آنها و اظهار نظر يك طرفه Subject variation 2 ـ Bias مشاهده ‌ گر (Observer) ( پژوهشگر ) مشاهده ‌ گر از نوع درمان و افراد مورد و شاهد اطلاع دارد و تحت تأثير آن اظهار نظر يك طرفه مي ‌ نمايد. 3 ـ Bias در ارزيابي و تجزیه تحلیل : نتیجه گیری از مطالعه ناخودآکاه تحت تأثیر افکار فرد تجزیه تحلیلگر قرار گیرد

41. طرح کلی کارآزمایی بالینی SP EC Study Group Outcome No Outcome SP = Study Population EC = Eligibility Criteria R = Randomize intervention T = Elapsed time T R Intervention No Intervention

42.  Bias and variability  Randomization: why and how?  Blinding: why and how?  General study designs

43.  The clinical trial is considered to be the “gold standard” in clinical research  Clinical trials provide the ability to reduce bias and variability that can obscure the true effects of treatment  Bias  affects accuracy  Variability  affects precision

44.  Bias: any influence which acts to make the observed results non-representative of the true effect of therapy  Examples: ◦ healthier patients given treatment A, sicker patients given treatment B ◦ treatment A is “new and exciting” so both the physician and the patient expect better results on A  Many potential sources of bias

45.  Variability: high variability makes it more difficult to discern treatment differences  Some sources of variability ◦ Measurement instrument observer ◦ Biologic within individuals between individuals  Can not always control for all sources (and may not want to)

46.  Groups must be alike in all important aspects and only differ in the treatment each group receives  In practical terms, “comparable treatment groups” means “alike on the average”

47.  If there is a group imbalance for an important factor then an observed treatment difference may be due to the imbalance rather than the effect of treatment Example: ◦ Drug X versus placebo for osteoporosis ◦ Age is a risk factor for osteoporosis ◦ Older subjects are enrolled in Drug X group ◦ Treatment group comparison will be biased due to imbalance on age

48.  We can not ensure comparability but randomization helps to balance all factors between treatment groups  If randomization “works” then groups will be similar in all aspects except for the treatment received

49.  Allocation of treatments to participants is carried out using a chance mechanism so that neither the patient nor the physician know in advance which therapy will be assigned  Simplest Case: each patient has the same chance of receiving any of the treatments under study

50.  Think of tossing a coin each time a subject is eligible to be randomized  HEADS:Treatment A  TAILS: Treatment B  Approximately ½ will be assigned to treatments A and B  Randomization usually done using a randomization schedule or a computerized random number generator

51.  May result in substantial imbalance in either ◦ an important baseline factor and/or ◦ the number of subjects assigned to each group  Solution: Use blocking and/or stratified randomization

52.  If we have two treatment groups (A and B) equal allocation, and a block size of 4, random assignments would be chosen from the blocks 1) AABB 4) BABA 2) ABAB 5) BAAB 3) ABBA 6) BABA  Blocking ensures balance after every 4th assignment

53.  To ensure balance on an important baseline factor, create strata and set up separate randomization schedules within each stratum  Example: if we want prevent an imbalance on age in an osteoporosis study, first create the strata “< 75 years” and “  75 years” then randomize within each stratum separately  Blocking should be also be used within each stratum

54.  Randomization is not always possible due to ethical or practical considerations  Some alternatives: ◦ Historical controls ◦ Non-randomized concurrent controls ◦ Different treatment per physician ◦ Systematic alternation of treatments  Sources of bias for these alternatives need to be considered

55.  Masking the identity of the assigned interventions  Main goal: avoid potential bias caused by conscious or subconscious factors  Single blind: patient is blinded  Double blind: patient and assessing investigator are blinded  Triple blind: committee monitoring response variables (e.g. statistician) is also blinded

56.  To “blind” patients, can use a placebo Examples ◦ pill of same size, color, shape as treatment ◦ sham operation (anesthesia and incision) for angina relief ◦ sham device such as sham acupuncture

57.  Patients who know they are receiving a new or experimental intervention may report more (or less) side effects  Patients not on new or experimental treatment may be more (or less) likely to drop out of the study  Patient may have preconceived notions about the benefits of therapy  Patients try to get well/please physicians

58.  Placebo effect – response to medical intervention which results from the intervention itself, not from the specific mechanism of action of the intervention Example: Fisher R.W. JAMA 1968; 203: 418-419 – 46 patients with chronic severe itching randomly given one of four treatments – High itching score = more itching TreatmentItching Score cyproheptadine HCI27.6 trimeprazine tartrate34.6 placebo30.4 nothing49.6

59.  Treating physicians and outcome assessing investigators are often the same people   Possibility of unconscious bias in assessing outcome is difficult to rule out  Decisions about concomitant/compensatory treatment are often made by someone who knows the treatment assignment   “Compensatory” treatment may be given more often to patients on the protocol arm perceived to be less effective

60.  In some studies it may be impossible (or unethical) to blind ◦ a treatment may have characteristic side effects ◦ it may be difficult to blind the physician in a surgery or device study  Sources of bias in an un-blinded study must be considered

61.  Many clinical trial study designs fall into the categories of parallel group, dose-ranging, cross-over and factorial designs  There are many other possible designs and variations on these designs  We will consider the general cases

62.  Parallel group designs

63.  Dose-Ranging Studies

64.  Cross-Over Designs

65.  Factorial Designs

66.  Subjects are randomized to sequences of treatments (A then B or B then A)  Uses the patient as his/her own control  Often a “wash-out” period (time between treatment periods) is used to avoid a “carry over” effect (the effect of treatment in the first period affecting outcomes in the second period)  Can have a cross-over design with more than 2 periods

67.  Advantage: treatment comparison is only subject to within-subject variability not between-subject variability  reduced sample sizes  Disadvantages: ◦ strict assumption about carry-over effects ◦ inappropriate for certain acute diseases (where a condition may be cured during the first period) ◦ drop outs before second period

68.  Appropriate for conditions that are expected to return to baseline levels at the beginning of the second period Examples: ◦ Treatment of chronic pain ◦ Comparison of hearing aids for hearing loss ◦ Mouth wash treatment for gingivitis

69.  Attempts to evaluate two interventions compared to a control in a single experiment (simplest case)  An important concept for these designs is interaction (sometimes called effect modification)  Interaction: The effect of treatment A differs depending upon the presence or absence of intervention B and vice-versa.

70.  Advantages: ◦ If no interaction, can perform two experiments with less patients than performing two separate experiments ◦ Can examine interactions if this is of interest  Disadvantages: ◦ Added complexity ◦ potential for adverse effects due to “poly-pharmacy”

71.  Example: Physician’s Health Study  Physicians randomized to: aspirin (to prevent cardiovascular disease) beta-carotene (to prevent cancer) aspirin and beta-carotene neither (placebo) Stampfer, Buring, Willett, Rosner, Eberlein and Hennekens (1985) The 2x2 factorial design: it’s application to a randomized trial of aspirin and carotene in U.S. physicians. Stat. in Med. 9:111-116.