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STA 105: Study Designs for Medical Research

Lecturer: Dr. Daisy DaiDepartment of Medical

Research

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Design will impact the study results and inferences

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When it comes to a design Consult statisticians Conduct literature review Assess strength and limitation of a

design Think outside of a box.

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Observational Studies

Prospective Cohort StudiesRetrospective Cohort Studies

Case-Control StudiesCross-Sectional Studies

Pre-post Tests

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Cohort Studies Cohort studies involve following

groups of subjects over time. The goal of the descriptive cohort

study is to describe the occurrence of certain of outcomes over time.

The analytic cohort study is to analyze associations between predictors and outcomes.

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Prospective cohort study The investigator defines the

sample and measures predictor variables before undertaking a follow-up period to observe outcomes.

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Nurses’ Health Study 1. Goal: to examine incidence and risk factors for common diseases in

women. 2. Assemble the Cohort: In 1976, the investigators obtained lists of

registered nurses aged 25 to 42 in the 11 most populous states and mailed them an invitation to participate in the study; those who agreed became the cohort.

3. Measure Predictor Variables and Potential Confounders. They mailed a questionnaire about weight, exercise and other potential risk factors and obtained completed questionnaires from 121,700 nurses. They send questionnaires periodically to ask about additional risk factors and update the status of some risk factors that had been measured previously.

4. Follow-up the Cohort and Measure Outcomes. The periodic questionnaires also included questions about the occurrence of a variety of disease outcomes.

5. Findings: Heavier women has a higher risk of breast cancer after menopause, and those who gained more than 20kg since age 18 had a twofold increased risk of developing breast cancer.

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Strengths and Weaknesses Time sequence of

risk factors Information on

baseline Complete measure

of risk factors and outcome variables

Recall error is minimized

Hard to make causal inference

Expensive Low incidence

rate and long waiting period for an event

Sensitive to attrition

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Retrospective cohort study The follow-up period and outcomes

have already occurred when the study takes place.

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Case Study – aortic aneurysm

1. Identify a Suitable Cohort. The investigators used the residents of Olmsted County, Minnesota. They searched a database of diagnoses made between 1980 and 1995 and found 133 residents who had a diagnosis of aortic aneurysm.

2. Collect Data about Predictor Variables. They reviewed patients’ records to collect gender, age, size of aneurysm, and risk factors for cardiovascular disease at the time of diagnosis.

3. Collect data about Subsequent Outcomes. They collected data from the medical records of the 133 patients to determine whether the aneurysm ruptured or was surgically repaired.

4. Findings: The 5-year risk of rupture was 20% and that women were 6.8 times more likely to suffer a rupture than men. 31% of aneurysms with diameters of more than 6cm ruptured, compared with none with diameters of less than 4cm.

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Strengths and Weaknesses Less costly Time saving

Existing data may be incomplete and inaccurate

Confounding factors

Some information might be outdated

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Strategies for Minimizing Losses during Follow-UpDuring enrollment Exclude those likely to be lost Obtain information to allow future trackingDuring follow-up Periodic contact with subjects to collect information,

provide results, express care, and so on. For those who are not reached by phone or mail,

consider home visit. At all times Treat study subjects with appreciation, kindness

and respect, helping them to understand the research question so they will want to join as partners in making the study successful.

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Cross-sectional Study

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Cross-sectional study The structure of a cross-sectional

study is similar to that of a cohort study except that all the measurements are made at about the same time, with no follow-up period.

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Case Study – Smoking in Movies

Goal: Investigate the association between actor smoking and teenage audience smoking

Selected the Sample: a random-digit-dial survey of 6,522 children aged 10 to 14 years.

Measured the Variables: They quantified smoking in 532 popular movies and for each subject asked which of a randomly selected subset of 50 movies they had seen. Subjects were also asked about a variety of covariates such as age, rage, gender, parental smoking and education, sensation-seeking (e.g., “I like to do dangerous things”) and self-esteem (e.g., “I wish I were someone else.”) The outcome variable was whether the child had ever tried smoking a cigarette.

Findings: Adjusted for age and other confounders, 38% of smoking initiation was attributable to exposure to movies in which the actors smoke.

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Strengths and Weaknesses One time

measure. Fast. Less costly.

Hard to make causal conclusions.

No time trend

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Case-Control Study

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Case-control Study In a case-control study, the

investigator (a) selects a sample from a population with the disease (cases), (b) selects a sample from a population at risk that is free of the disease (controls), and (c) measures predictor variables.

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Case Study Objectives: Because intramuscular (IM) vitamin K is given routinely

to newborns in the United States, a pair of studies reporting a doubling in the risk of childhood cancer among those who had received IM vitamin K caused quite a stir. To investigate this association further, German investigators

Selected the Samples: 107 children with leukemia from the German Childhood Cancer Registry. 107 children matched by sex and date of birth and randomly selected from children living in the same town as the case at the time of diagnosis.

Measure the Predictor Variable. Reviews medical records to determine which cases and controls had received IM vitamin K in the newborn period.

Findings: 69 of 107 cases (64%) and 63 of 107 controls (59%) had been exposed to IM vitamin K with an odds ratio =1.2 and 95% CI = 0.7 – 2.3. Therefore, the study did not confirm the existence of an association between the receipt of IM vitamin K as a newborn and subsequent childhood leukemia.

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Strengths and Weaknesses Reduce sample

size. Reduce the

variation within the pair

Only study one outcome.

Susceptible to bias.

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Nested Case-Control and Case-Cohort Studies In a case-control study, the investigators (a)

identifies a cohort with banked specimens, images or information; (b) identifies those participants who developed the outcome during follow-up (the cases); (c) selects the rest of the cohort (the controls); and (d) measures predictor variables in cases and controls.

The nested case-cohort approach is the same design except that the controls are a random sample of all the members of the cohort regardless of outcomes.

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Sex hormones in patients with breast cancer Identify a Cohort with Banked Samples. The

investigators used serum and data from the Study of Osteoporotic Fractures, a prospective cohort of 9,704 women age 65 and older.

Identify Cases at the End of Follow-up. Based on responses to follow-up questionnaires and review of death certificates, the investigators identified 97 subjects with a first occurrence of breast cancer during 3.2 years of follow-up.

Select Controls. The investigators selected a random sample of 244 women in the cohort who did not develop breast cancer during that follow-up period.

Measure Predictors on Baseline Samples from Cases and Controls. Levels of estradiol and testosterone were measure in serum specimens from the baseline examination that had been stores at – 190°C by laboratory staff who were blinded to case-control status.

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Case Study To determine whether significant neonatal jaundice or

dehydration has any significant adverse effects on neurodevelopment, investigators from UCSF and the Northern California Kaiser Permanente Medical Care Program (5) undertook a triple-cohort study. The basic steps in performing the study were to

Identify Cohorts with Different Exposures. The investigators used electronic databases to identify term and near-term newborns who (1) had a total serum bilirubin level of ≥25 mg/dL, or (2) were readmitted for dehydration with a serum sodium of ≥150 mEq/L or weight loss of ≥12% from birth, or (3) were randomly selected from the birth cohort.

Determine Outcomes: The investigators used electronic databases to search for diagnoses of neurological disorders and did full neurodevelopmental examinations at the age of 5 for consenting participants.

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Advantages and Disadvantages of the Major Observational Designs

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Randomized Controlled Trials

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Randomized controlled trial: (RCT)

A study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. The control may be a standard practice, a placebo ("sugar pill"), or no intervention at all. RCTs seek to measure and compare the outcomes after the participants receive the interventions.

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Case Study: FEV1 Changes

A new compound, ABC-123, is being developed for long-term treatment of patients with chronic asthma. Asthma patients were enrolled in a double-blind study and randomized to receive daily oral or a placebo

for 6 weeks. FEV1 after 6-week treatment

Placebo Test

asthmatic patients

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FEV1 DataTest Group

Patient ID Baseline week 6

101 1.35 n/a

103 3.22 3.55

106 2.78 3.15

108 2.45 2.3

109 1.84 2.37

110 2.81 3.2

113 1.9 2.65

116 3 3.96

118 2.25 2.97

120 2.86 2.28

121 1.56 2.67

124 2.66 3.76

Placebo Group

Patient ID Baseline week 6

102 3.01 3.9

104 2.24 3.01

105 2.25 2.47

107 1.65 1.99

11 1.95 n/a

112 3.05 3.26

114 2.5 2.55

115 1.6 2.2

117 .77 2.56

119 2.06 2.9

122 1.71 n/a

123 3.54 2.92

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P-value P-value

What is the difference

between std and std error?

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Mean and Error Bar

Conclusion: As compared to placebo, the new drug did not show any effect on FEV1.

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Paired t-testCompare the means of a normally distributed interval dependent variable for two related groups.

Test Group

Patient ID Baseline week 6

101 1.35 n/a

103 3.22 3.55

106 2.78 3.15

108 2.45 2.3

109 1.84 2.37

110 2.81 3.2

113 1.9 2.65

116 3 3.96

118 2.25 2.97

120 2.86 2.28

121 1.56 2.67

124 2.66 3.76

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P-value

Conclusion: For subjects on the new drug,

FEV1 at week 6 is significantly higher than

baseline.

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Strengths and Weaknesses RCTs are quantitative,

comparative, controlled experiments in which investigators study two or more interventions in a series of individuals who receive them in random order. The RCT is one of the simplest and most powerful tools in clinical research.

Ethics Recruit of

participants Cost

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Case Studies and Discussions

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Probiotics A recent study identified 63 medical trials that compared

probiotics to placebo or to no probiotics for treating short-term diarrhea in 8,014 people, mostly children. Probiotics, commonly found as a supplement in many yogurts and other foods, are thought to fight diarrhea in a number of ways—perhaps by competing with the pathogens for nutrients or by spurring a stronger immune response. Whatever the reasons, probiotic treatments shortened the course of diarrhea in nearly all the studies, and by an average of 25 hours. (The average total duration of diarrhea in the studies ranged from 39 to 161 hours.) Patients taking probiotics were also 59% less likely to experience diarrhea lasting longer than three days.

Caveat: The trials tested a range of probiotic strains and doses; the meta-analysis could not determine whether certain strains were more effective than others.

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Cataracts Neither vitamin E nor vitamin C protests men against cataracts, according

to a study in the Archives of Ophthalmology. The antioxidant vitamins had once been candidates to reduce the risk of developing cataracts (cloudy areas in the eye that can impair vision), since they already play a protective role within eye membranes. Though several recent randomized trials have found little evidence in favor of the treatment, none have followed their participants for more than 6½ years. In this study, researchers randomly assigned 11,545 male doctors to take a daily dose of vitamin C or placebo daily. The same group was also randomly assigned to receive either vitamin E or placebo every two days. After an average of eight years of follow-up, 1174 of the participants developed cataracts, evenly spread between the vitamin and placebo groups. The vitamins also had no effect on any subtype of cataract.

Caveat: Doctors might have healthier diets than the general population, and thus might derive less benefit from vitamin supplementation. It’s also possible that the protective effects of vitamins E and C only emerge after a period even longer than eight years.

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Fish Oil Omega-3 fatty acids, such as those found in fish oil, don’t prevent atrial

fibrillation from recurring, according to a study in the Journal of American Medical Association. Researchers recruited 542 patients who had been diagnosed with a short-term form of atrial fibrillation. Each patient was randomly assigned to take daily capsules of either omega-3 fatty acids or placebo for six months. Though omega-3s have been associated in observational studies with improved heart health, they provided little benefit in this study: By the end of the six months, atrial fibrillation had returned in 52% of the patients taking omega-3s and 48% of those taking placebo, a statistically insignificant difference. Omega-3s also did not prevent atrial fibrillation recurrences among an additional 121 patients who had a more persistent form of the condition.

Caveat: It’s possible that omega-3s protect against atrial fibrillation only in the longer-term. Because the study recruited only otherwise healthy patients, the results might not apply to the elderly, patients with other forms of heart disease, or those who have recently had heart surgery.

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Satiety Study

Satiety is subjective, variable and difficult to measure. Two experiments were conducted to assess the impact of Crossover Design and Parallel Design to the same stimuli and speculate the sensitivity and reliability of continuous and dichotomous measures in satiety studies.

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Problem Statements Visual analogue scale has been widely used to measure

satiety. However, the outcome variables were often noisy and sensitive to design manipulation.

Many psychometric rating systems have been developed to measure satiety and sensation. But there are few experiments conducted to compare different measures.

In this work, we conduct two experiments to answer following questions:

Is continuous measure superior to dichotomous measure?

What factors do we consider in selection between cross-over design and parallel design?

What are the halo effects in cross-over design?

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MethodsExperiment 1: Crossover design (n=23) Frozen meals with different

sensation agents, Control and Test, were randomly assigned to subjects.

Experiment 2: Stratified Parallel Design. Subjects were stratified by

baseline hunger and randomized to Control (n=27) and Test (n=29).

We provided a reduced calorie diet. By comparing the results with and without this experiential manipulation, we can assess the degree of influence from this confounding factor and also evaluate the satiety measures’ sensitivity and robustness.

Other conditions remained same as Experiment#1.

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In both experiments, satiety was measured by Continuous Hunger Likert Score:

Hunger, fullness, thirst, desire for a snack, thirst and general mood were evaluated at baseline and every 30 minutes for up to 5 hours post meal using 11-point Likert scale.

Dichotomous Measure: Subjects were asked whether they would decline their favorite food or dessert at baseline and every 30 minutes for up to 5 hours post meal.

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Results Significant treatment and time effects were found using

Dichotomous Measure in both Crossover Design (Figure 1) and Stratified Parallel Design (Figure 2). Only the time effect but no treatment effect was detected in Hunger and Fullness Likert Scales measured every half hour (Figures 3 & 4).

Both Dichotomous Measure and continuous Likert Measures encountered the adaptation effect in Crossover Design (Experiment # 1): the satiety perception was significantly different between two visits after adjusting for the treatment effect.

The Hunger Likert Scores had an undesirable treatment by day of visit interaction at baseline, which indicates Continuous Measures could be less robust or more variable as compared to Dichotomous Measure (Figure 3).

In Experiment #2, the stratification technique objectively calibrated the psychometric ratings among subjects at baseline. Also thanks to the removal of the adaptation effect, Hunger Liker Scores under Stratified Parallel Design were cleaner (Figure 4).

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Conclusions Our study suggests that discrete

measures, with less psychological/rating variability, could be more powerful and robust than continuous measures in assessment of small to moderate satiety effects. A Stratified Parallel Design might help reduce the experimental halo for studies with confounding adaptation effects.

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Summary

Observational Studies vs. Randomized Controlled Trials (RCTs)

Cohort Studies vs. Cross-Sectional Studies Prospective Studies vs. Retrospective

Studies Case-control Studies and Pre-Post Tests

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References Designing Clinical Research 3rd

edition by Hulley et al.