Sumarni Faculty of Medicine & Public Health Tadulako University DESAIN PENELITIAN Sumarni Faculty of Medicine & Public Health Tadulako University

Proses Ilmiah Problem Hipotesis Prediksi Uji Kesimpulan Bukan

Pertanyaan Penelitian HASIL PENELITIAN Pertanyaan Penelitian Tujuan Hipotesis Nilai sebenarnya + = HASIL Kesalahan

Kesalahan Kesalahan sistematis/bias Kesalahan acak Kesalahan sistematis dihindari dengan penggunaan metodologi dan desain penelitian yang tepat Kesalahan acak dihindari dengan penggunaanstatistik yang tepat

KESEIMBANGAN ANTARA VALIDITAS & FISIBILITAS ? Desain Metodologi Statistik Fisibilitas Validitas Proposal penelitian

Alam nyata Alam impian Problem Hipotesis Pembuktian Prediksi Hasil Analisis Data Interpretasi Kesimpulan Hipotesis yang baru

DESAIN PENELITIAN Cross-sectional Case control Perlakuan Paparan alamiah Eksperimental Laboratorium Binatang Percobaan Manusia Observasional Deskriptif (Tidak ada perbandingan kelompok) (Ada perbandingan kelompok) Analitik Cohort Kalau deskriptif tidak menggunakan tanda panah Kalau analitik menggunakan tanda pana (menandakan adanya hubungan) Causal comparative correlational Metaanalisis

O E DESAIN PENELITIAN MENURUT WAKTU Retrospektif Case-control Prospektif Alamiah Cohort Perlakuan Eksperimental Sekarang Y.a.d. Lampau Cross sectional Case control = waktu dan kasusnya berjalan bersamaan Alamiah = misalnya pengaruh asi eksklusif terhadap IQ anak

Case-Control Study

Schematic diagram of case control study Time Onset of study Cases Controls Exposed Unexposed Direction of inquiry

Odds & Odds Ratio (OR) Odds: probabilitas terjadinya suatu keadaan dibandingkan dengan probabilitas tidak terjadi Odds ratio: ukuran hubungan paparan dengan kejadian penyakit untuk mengetahui seberapa besar resiko suatu paparan sehingga menyebabkan penyakit dibandingkan bila tidak terkena paparan

Case control study Case Control Exposed a b Unexposed c d Odds ratio = ad / bc Odds = prob of even/ 1- Prob of even

Reye’s syndrome Occurs in children 2-16 yrs as a serious complication of influenza B or less often – influenza A or varicella zoster infection. It begins with 1-2 day of nausea and vomiting followed by CNS symptoms, including changes in mental status, that range from lethargy to coma and encompass delirium and seizure. Elevated serum transaminase level and elevated amonia concentration, and hepatomegaly are common

Aspirin use during viral illness among children and subsequent risk of developing Reye’s Treatment Reye’s syndrome + - Aspirin use 28 35 No aspirin use 2 25 Odds ratio = 28 x 25 / 35 x 2 = 10

Interpretation of OR The odds of having disease in question are OR times greater among those exposed the suspected risk factor For rare disease ( e.g. chronic disease which have prevalence < 10%) OR approximates RR That is, the risk of the disease is approximately OR times greater among those exposed to the suspected risk factor RR = [P(D+/E+)] : [P(D+/E-)] = [a/(a+b)] : [c/(c+d)]. For rare disease a and c are small relative to b and d. Thus a/b approximates a/(a+b) and c/d approximates c/(c+d)

Interpretation of OR….. cont The larger the value of OR, the stronger the assoociation. When the value of OR is close to 1, the disease and exposure to the risk factor are unrelated Value of OR < 1 indicate a negative association

OR and study design Since P(D+/E+), P(D+/E-), P(D-/E+) and P(D-/E-) can be estimated from result of a cohort or an experimental study, OR can be calculated directly these study designs are employed

OR in a case-control study The conditional probability of disease P(D+/E+), P(D+/E-), P(D-/E+) and P(D-/E-) can not be calculated directly from the result of a case control study Estimates of the conditional probability of exposure can be obtained in a case-control study.

Oral Contraceptive Use & Breast Cancer Problem: Is OC associated with the risk of breast cancer? Research Hypothesis: There is an association between OC use and breast cancer Cases: All women 20-54 years old with newly diagnosed breast cancer who reside in one of eight geographic regions in the United States. The women were identified through population-based tumor registries Controls: Women of the same ages selected at random from the general population of the same region and the same period when cases were diagnosed

Selection of Cases Usually based on outcome Incident outcomes Prevalent outcomes

Selection of Controls Should be selected according to predetermined criteria to ensure the absence of outcome May be better to choose subject with similar referral, surveillance, and other factors capable of distorting the study sample

Exposure The primary exposure of interest is prior exposure, not contemporaneous one Need biologic model for how exposure causes outcome Dose, duration, and period of exposure should be specified ahead of time

Case-Control Study Advantages Disadvantages Statistically more efficient when outcome are rare Quicker when outcome are delayed Less costly Disadvantages Enhanced potential for sample distortion Exposure ascertainment more prone to error and bias

COHORT STUDY

Cohort Study Cohort: a group of people that exposed to particular exposure in a period of time Cohort study can be conducted prospectively or retrospectively

Cohort study Retrospective Cohort, both exposure and outcome observed have been occurred before study conducted Prospective Cohort study, subject of the study may already been exposed or not yet been exposed when a study started, but the outcome not yet been available

Retrospective and prospective cohort study Disease No disease Exposed Unexposed Disease No disease Exposed Unexposed Past Present Future

Requirement Exposure criteria is clear and specific Intensity Duration Regularity Variability Duration of follow-up Outcome measurement: blind, objective

Schematic diagram of cohort study Time Onset of study Disease No disease Exposed Unexposed Direction of inquiry

Cohort study Disease + - Exposed a b Unexposed c d Relative risk (risk ratio) = a/(a+b) : c/(c+d)

Relationship between 10 minute Apgar scores and risk of death in the first year of life among children with birth weights of at least 2500 g Death + - Apgar score 0-3 42 80 4-6 43 302 Relative risk (risk ratio) = 42/(42+80) : 43/(43+302) = 2.8

Interpretation of RR The disease is RR times more likely to occur among to exposed to the suspected risk factor The larger the value of RR, the stronger the association The value of RR close to 1 indicate that the disease and exposure to the risk factor are unrelated Value of RR < 1, indicate a negative association

RR and study design RR can be directly calculated only in a cohort or experimental study Because incidence can not be estimated from a case control study, RR can not be calculated directly. Under some circummctances, the RR in a case control study can be estimated by OR

Result of hypothetical cohort study Disease present Disease absent Total Exposed a b a + b Non exposed c d c + d a + c b + d RR = a/(a+b) c/(c+d) OR = a/b c/d

Strength of the association Relative risk (RR) = Risk of disease if exposed to risk factor Risk of disease if not exposed to risk factor Odds ration = Odds that exposed individual will have disease Odds that non-exposed individual will have disease Odds of disease = P(disease)/1 – P (disease) = P (disease) / P (no disease)

Pemilihan Subjek kasus dan kontrol Keduanya diambil dari populasi yang sama Keduanya belum menderita penyakit yang akan diteliti saat penelitian dimulai Karakteristik sampel kasus dan sampel kontrol sama Ada informasi yang ekual antara kedua grup Kedua grup harus dapat dihubungi dan dapat di follow up

Contoh beberapa penelitian

CRP and BMI predict outcome in end-stage respiratory failure, Cano et al, 2004, Chest, 126: 540-546 Menentukan faktor prognosis kematian dan kesakitan utk penyakit pernafasan stadium akhir Penelitian Cohort (COPD: 42,8%, restrictive disorder 36,3%, campuran 13,5%, bronkiektasis 7,4%) CRP, BMI, PaO2 dan kortikosteroid oral mrpk prediktor independen kemampuan hidup

Graf failure < 0,5 g/hr: 13,3% 0,5-1 g/hr: 25,3% > 1 g/hr: 45,8%

HR: 4,58 HR: 7,03

Oscarson et al., menyimpulkan Kenaikan kadar TnT pasca operasi memberi risiko 15 kali kematian pd th pertama Pemeriksaan TnT untuk lansia (sering terjadi silent myocardial ischemia) pd masa perioperatif bermanfaat utk menilai risiko kematian pd tahun pertama pasca operasi

Anti p53

Ekspresi p53

Ekspresi keduanya

Seronegative myasthenia gravis: disease severity and prognosis (Romi et al., 2005, European Journal of Neurology, 12: 413-418)

Anti reseptor asetilkolin berkorelasi dengan derajat Myastenia Gravis

CD2+ Vs CD2- CD2+APL CD2-APL Hitung lekosit 34,5 ±13,1/L 6,8 ±2,1/L Karakteristik morfologis 50% 0% Angka remisi sempurna 87% Kematian 66,7 13

(Overall Survival)

Hasler G ., et al., Sleep. 2004 Jun 15;27(4):661-6 The association between short sleep duration and obesity in young adults: a 13-year prospective study Hasler G ., et al., Sleep. 2004 Jun 15;27(4):661-6

The association between short sleep duration and obesity ……….. STUDY OBJECTIVES: to test the hypothesis that short sleep duration is associated with obesity and weight gain during young adulthood. DESIGN: Prospective single-age cohort study of young adults. Information was derived from 4 interviews when participants were ages 27, 29, 34, and 40 years. SETTING: Community setting. PARTICIPANTS: 496 young adults.

The association between short sleep duration and obesity ……. RESULTS: This study showed an association between short sleep duration and obesity (at age 27 years, odds ratio: 7.4, 95% CI: 1.3-43.1) and a negative association between sleep duration and body mass index in young adults. These associations persisted after controlling for a variety of potentially confounding variables, including family history of weight problems, levels of physical activity, and demographic variables. Associations between sleep duration and obesity diminished after age 34 years.

The association between short sleep duration and obesity …….. There was a trend (P = .08) for average change rate of weight gain to be negatively associated with average change rate of sleep duration. CONCLUSIONS: Because sleep duration is a potentially modifiable risk factor, these findings might have important clinical implications for the prevention and treatment of obesity.

Smoking cessation in a population-based cohort study Garcia M .et al., Arch Bronconeumol. 2004 Aug;40(8):348-54

Smoking cessation in a population-based cohort study Objective: To study the incidence rates and the determinants of smoking cessation in a population-based cohort. Material and methods: We used data from the Cornella Health Interview Survey Follow-up Study. Subjects who declared they were daily smokers at baseline (1994) and had complete follow-up, with information on smoking status in 2002, entered into analysis. We calculated incidence rates and the relative risks of cessation (with 95% confidence intervals) using the Cox model.

Smoking cessation in a population-based cohort study Results: Out of 353 daily smokers, 100 quit smoking during the follow-up period (cumulative incidence of 28.3%). The incidence rate of cessation was higher among men (42.34 per 1000 person-years) than among women (24.97 per 1000 person-years), with a relative risk of cessation of 1.69 (95% confidence interval, 1.02-2.79) for men. Age and level of education were associated with a higher relative risk of quitting in men.

Smoking cessation in a population-based cohort study Conclusions: The main determinants for smoking cessation are sociodemographic (sex, age, and level of education).

Factors predisposing to perinatal death related to uterine rupture during attempted vaginal birth after caesarean section: retrospective cohort study Smith GC ., et al., BMJ. 2004 Jul 19

Factors predisposing to perinatal death related to uterine rupture ………. OBJECTIVE: To determine the factors associated with an increased risk of perinatal death related to uterine rupture during attempted vaginal birth after caesarean section. DESIGN: Population based retrospective cohort study. SETTING: Data from the linked Scottish Morbidity Record and Stillbirth and Infant Death Survey of births in Scotland, 1985-98

Factors predisposing to perinatal death related to uterine rupture …….. PARTICIPANTS: All women with one previous caesarean delivery who gave birth to a singleton infant at term by a means other than planned repeat caesarean section (n=35 854). Main outcome measures All intrapartum uterine rupture and uterine rupture resulting in perinatal death (that is, death of the fetus or neonate).

Factors predisposing to perinatal death related to uterine rupture ………. RESULTS: The overall proportion of vaginal births was 74.2% and of uterine rupture was 0.35%. The risk of intrapartum uterine rupture was higher among women who had not previously given birth vaginally (adjusted odds ratio 2.5, 95% CI 1.6 to 3.9, P<0.001) and those whose labour was induced with prostaglandin (2.9, 2.0 to 4.3, P<0.001).

Factors predisposing to perinatal death related to uterine rupture………. Both factors were also associated with an increased risk of perinatal death due to uterine rupture. Delivery in a hospital with <3000 births a year did not increase the overall risk of uterine rupture (1.1, 0.8 to 1.5, P=0.67). However, the risk of perinatal death due to uterine rupture was significantly higher in hospitals with <3000 births a year (one per 1300 births) than in hospitals with >/=3000 births a year (one per 4700; 3.4, 1.0 to 14.3, P=0.04).

Factors predisposing to perinatal death related to uterine rupture……… CONCLUSION: Women who have not previously given birth vaginally and those whose labour is induced with prostaglandin are at increased risk of uterine rupture when attempting vaginal birth after caesarean section. The risk of consequent death of the infant is higher in units with lower annual numbers of births.

Advantages Direct calculation of risk ratio (relative risk) May yield information on the incidence of disease Clear temporal relationship exposure and disease Particularly efficient for study of rare exposures Can yield information on multiple exposures Can yield information on multiple outcomes of a particular exposure Minimizes bias Strongest observational design for establishing cause and effect relationship

Disadvantages Time consuming Often requires a large sample size Expensive Not efficient for study of rare diseases Losses to follow-up may diminish validity Changes over time in diagnostic methods may lead to biased results

CROSS SECTIONAL

Penelitian potong lintang Deskriptif Mengukur prevalensi suatu penyakit pada suatu populasi Analitik Mengukur hubungan antar faktor resiko dengan kejadian suatu penyakit

Struktur Penelitian Mirip cohort, tetapi pengukuran dilakukan sekali Tidak ada follow-up Cocok untuk menjelaskan variabel-variabel secara deskriptif dan juga pola distribusinya Dapat juga untuk menguji hubungan

Penelitian potong lintang Pertanyaan penelitian Kriteria populasi penelitian (target/accessible population) Teknik pengambilan sampel

- - + + Chlamydia 10 40 50 Kontrasepsi oral 50 45 5 15 85 100 Contoh Chlamydia + - + 10 40 50 Kontrasepsi oral - 50 45 5 15 85 100 Prevalensi = 15/100 Prevalensi relatif 10/5 = 2

Prevalensi Adalah jumlah kasus yang terjadi dibandingkan dengan jumlah subjek yang diteliti Bermanfaat bagi: Perencana program kesehatan Klinisi

Associations in Clinical Medicine To define associations between disease and predisposing or causal factor To discover a cause-and-effect relationship that will result in effective treatment and prevention strategies

Risk factor A condition, physical characteristic, or behaviour that increase the probability that a currently healthy individual will develop a particular disease

Type of risk factors Environmental risk factors Behavioral, or life-habit, risk factors Social risk factors Genetic risk factors

Exposure An individual who has contact with or who manifest the risk prior to becoming ill Exposure may occur at a single point in time More commonly, exposure is chronic (e.g., hypertension). Measure of chronic exposure include current dose, total cumulative dose, years of exposure, and years since the first exposure

Relationship of risk factors to disease A risk factor may be a causal factor of the disease in question or merely a marker for the increased probability of disease For example, while poor prenatal care and drug use constitute causal factors for neonatal mortality, socioeconomic status would be considered a marker for neonatal mortality

Kelebihan penelitian potong lintang Tanpa menunggu Memberi gambaran tentang prevalensi atau faktor resiko Networks of causal links Dapat dimasukkan dalam penelitian cohort atau perlakuan

Kelemahan penelitian potong lintang Sulit menetapkan hubungan kausal Kurang praktis untuk penelitian terhadap kasus yang jarang

Serial survey Merupakan seri penelitian-penelitian potong lintang pada satu populasi Untuk melihat pola perubahan dalam periode waktu tertentu Bukan cohort

Study Design Ranking Design Strongest Experimental Prospective cohort Retropective cohort Case control Weakest Cross-sectional

Experimental vs observational studies In experimental studies, the investigator controls the assignment of study subjects to experimental and control groups and actively manipulates one variable (independent variable) while observing the resultant in another (dependent variable) Example, study on caffein effect on systolic blood presure

Effect of caffein --- sistolic BP R Placebo High dose caffein Low dose caffein SBP + SBP - 6 months

Hill’s criteria for causality Used to evaluate the plausibility of putative cause-and-effect relationship: Study design Strength of the association Consistency Correct temporal relationship Dose-response relationship between exposure and severity of the outcome Plausibility Specificity Analogy