Observational Study Designs and

Studies of “Tests”

Warren Browner August 2011

Outline A historical perspective Why choose a particular design Review common designs

Cohort Case-control Cross-sectional

Studies of diagnostic and prognostic tests

Practice

A bit of historical perspective

Clinical epidemiology Uses epidemiologic approaches,

concepts, and terms in clinical research

Bias Sampling Rates (hazards), risks, odds (and their

ratios) Incidence vs. prevalence

A thought experiment Half of all trainees at academic medical

centers enter a cognitive specialty (IM, FP, Peds, etc.) and half enter a procedural specialty (everyone else)

The average duration of cognitive specialty training is 3 years, and of procedural training is 6 years

Over time, what percentage of all residents are in procedural specialties?

There are many kinds of studies

And as many ways to classify them But (IMHO) physiology matters

more than anatomy

Today we are just going to talk about observational studies (and studies of medical tests)

Key elements of study design

Will there be comparisons? Will you sample on the outcome? Will there be any follow-up?

We will come back to these points

Why do an observational study?

To describe something Attributes (predictors) Outcomes

To look for associations Between predictors and outcomes

After adjusting for (confounders) Among predictors

To “suggest” causality

What if there aren’t any comparisons?

Descriptive study Not much more to say about the design Sometimes description is all that’s

needed

But most studies make comparisons Analytic studies

Observational analytic studies

Causality (predictor causes outcome) usually matters

Observing may be the only option for studying risk factors for disease Sex, race, genetics, SES, habits

Why choose a particular design?

Resources (time and money)

Frequency of the outcome (disease)

Quality and comprehensiveness of available data

Resources

Time Your RQ: is childhood reading level is

associated with late-life dementia? Your RQ: is duration of invasive

cardiology procedure associated with stent patency at 5 years?

Resources

Money Your RQ: are estrogen levels

associated with the recurrence of breast cancer over a 2-year period in women with early-stage breast cancer?

Frequency of the outcome

Rare disease Your RQ: is intrauterine exposure to

radiation while flying associated with childhood leukemia?

Your RQ: is consuming “energy drinks” associated with subarachnoid hemorrhage?

Quality of the available data

Not measured Your RQ: is bone density associated

with stroke independent of systolic blood pressure?

New (or better) measurement Your RQ: is balance associated with

hip fracture?

The main analytic designs

Cohort Case-control Cross-sectional

The main analytic designs

Cohort Case-control Cross-sectional

Will you sample on the outcome? Will there be any follow-up?

The main analytic designs

Cohort Assemble a group, make measurements,

and follow-them Case-control

Assemble two groups based on outcome (cases and controls), make measurements

Cross-sectional Assemble a group, make measurements

The cohort design

Assemble a group, make measurements, and follow-them

Find a group in which measurements were made, and then follow them

Find a group in which measurements were made, and who were already followed

The case-control design

Assemble two groups (cases and controls), make measurements, usually of attributes from the past

Assemble two groups (cases and controls) in whom measurements were made in the past Usually in a cohort in which the cases

occurred during follow-up (vs. non-cases)

The cross-sectional design Assemble a group, make measurements Find a pre-assembled group, make

measurements Find a pre-assembled and pre-measured

group

All measurements made at “same time”

Review of the main designs

Cohort Case-control Cross-sectional

Will you sample on the outcome? Will there be any follow-up?

What is follow-up? Time that passes…

Between when the predictors were measured and the outcomes occurred?

Between when the predictors occurred and the outcomes occurred?

Between when the predictors were measured in the study and the outcomes occurred?

Longitudinal study

Two more terms

Prospective Retrospective

Which one is better?

Prospective cohort studies

Measure (most of) what you want Then follow the subjects

Must wait for outcomes to occur Can take a long time Usually expensive

Enrollment, measurement, ascertainment May not be enough outcomes

Retrospective cohort and case-control studies

Look for situations in which the predictors and outcomes have already occurred

Cannot necessarily measure what you want

May not need to enroll anyone

Digression: a little epidemiology

Incidence New cases of an outcome that occur Can measure in a cohort study

Prevalence Cases that exist at a given time Can measure in a cross-sectional study

Neither can be measured in a case-control study

Epidemiology, round 2

Incidence = new cases (n = 20) that occur in a population at risk (n = 100) followed for a given period of time

At risk means can’t already have the outcome, but could get it Risk = new ÷ population at risk (0.20) Rate = new ÷ person-time (≈ 0.22/p-y) Odds = new ÷ everyone else (0.25)

Epidemiology, round 2a

Incidence = new cases (n = 3) that occur in a population at risk (n = 100) followed for a given period of time

At risk means can’t already have the outcome, but could get it Risk = new ÷ population at risk (0.03) Rate = new ÷ person-time (≈ 0.03/p-y) Odds = new ÷ everyone else (≈ 0.03)

Epidemiology, teaching point

For a rare outcome Odds ≈ Rate ≈ Risk Therefore:

Odds ratio ≈ Rate ratio ≈ Risk ratio

This is the secret behind why case-control studies can estimate relative risks (risk ratios)

A thought experiment Half of all trainees at academic medical

centers enter a cognitive specialty (IM, FP, Peds, etc.) and half enter a procedural specialty (everyone else)

The average duration of cognitive specialty training is 3 years, and of procedural training is 6 years

Over time, what percentage of all residents are in procedural specialties?

Answer 100 residents, 50 start in each area The cognitive specialists take 3 years, so

the 50 residents contribute 150 resident-years

The proceduralists take 6 years, so the 50 residents contribute 300 resident-years

Of the total of 450 resident-years, 2/3 are proceduralists, so at any given time, 2/3 of residents are proceduralists

Who cares?

A cross-sectional study that looked at all trainees might conclude that 2/3 choose proceduralist programs

How might you address this problem?

Bonus: What is this an example of?

Studies of medical tests Outcome can be disease (yes/no)

or prognosis (did well, did poorly)

Causality irrelevant No one thinks an abnormal test

causes the disease

Studies of medical tests Not enough to show that test

result is associated with outcome

Need to show that it’s useful at separating those with outcome from those without

Showing usefulness

Study subjects resemble patients in whom the test might be used Test for pancreatic cancer should not

compare patients with weight loss and belly pain to healthy medical students

Test for bipolar disease should not compare patients with mood swings to SF Giants fans

Showing usefulness Attributes of the test itself

Reproducible, accurate, inexpensive, safe

Will it affect decisions and improve outcomes (is it better than current tests)?

Blinded evaluation of test results

Defining usefulness

Test operating characteristics Sensitivity, specificity, predictive

value positive, predictive value negative, likelihood ratios

All of these terms are confusing Worth learning likelihood ratios

How I remember them

Sensitivity = PID Positivity in disease A decent value is 70% or more

Specificity = NIH Negativity in health A decent value is 70% or more

How I remember them

Likelihood ratio = ratio of likelihoods WOWO: the likelihood of a particular

test result in patients with disease over (÷) the likelihood of that same test result in patients without disease

A decent LR(+) is ≥ 2 A decent LR(-) is ≤ 0.5

Epidemiology, final round

Odds Ratio = LR(+) ÷ LR(-)

Let’s do an example

A psychiatry resident notices that many of her schizophrenic patients don’t use her name, which she calls the “Anonymous MD” sign. She systematically records visits from 40 patients followed in the psychiatry clinic with schizophrenia and finds the sign in 30 of them.

When she records visits of 50 control patients in the general internal medicine clinic, she finds that only 8 of them have the sign. She enthusiastically reports these findings in the New Orleans Magazine of Medicine.

What did she report as the sensitivity and specificity of the “Anonymous MD” sign for the diagnosis of schizophrenia?

What about the LR(+) and LR(-)?

Sensitivity = Positivity In Disease (PID) = 30/40 = 75%

Specificity = Negativity In Health (NIH) = 42/50 = 84%

LR(+) = 30/40 ÷ 8/50 = 0.75 ÷ 0.16 = 4.7

LR(-) = 10/40 ÷ 42/50 = 0.25 ÷ 0.84 = 0.29

Incensed, you write a letter to the editor of the Magazine, pointing out the major problems with the design of the study. What do you write about?

Points you might make• “Anonymous MD” sign could be seen in any type of

psychiatric disease. It could even be a sign of better prognosis or clinic attendance in schizophrenics.

• Subjects not representative of patients in whom sign might be clinically useful.

• Lack of blinding.

• Low prevalence of schizophrenia would mean a high false-positive rate in most populations.

• Medicine patients might “over-use” their MD’s name.

• Age/sex differences in patients and controls?

The last paragraph of your letter proposes a better design to evaluate the usefulness of the “Anonymous MD” sign. What did you suggest?

Assess sign prospectively and blindly in all patients who present for evaluation of a psychiatric condition in which schizophrenia is a diagnostic possibility.

Determine disease status without knowing about presence or absence of “Anonymous MD” sign.

What’s the Problem?An investigator is studying whether there is an association between drinking coffee and cancer of the pancreas. He assembles a group of patients with pancreas cancer and a group of patients with other gastrointestinal diseases, and asks them about their coffee-drinking habits during the previous ten years. All of the patients have undergone a GI evaluation, so the investigator is reasonably certain who has and who does not have pancreas cancer.

He finds that coffee drinking was substantially more common in the patients with pancreas cancer.

What’s the Problem? (cont’d)

• What kind of study is this?

• What’s wrong with this study? How could it be fixed?

• Bonus: Where was it published? Where was it performed?

Time for questions????