Classification and Bias of Clinical Research

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Classification and Bias of Clinical Research

• Rick Chappell, Ph.D.
• Professor,
• Department of Biostatistics and Medical
  Informatics
• University of Wisconsin Medical School

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Good Ethics is Good Science

• If a research study is so methodologically
  flawed that little or no reliable information
  will result, it is unethical to put subjects at
  risk or even to inconvenience them through
  participation in such a study. Clearly, if it
  is not good science, it is not ethical.
• - U.S. Dept. of Health and Human Services,
  Policy for Protection of Human Subjects (45 CFR
  46, 1/1/92 ed.)

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Types of Studies Classified by Temporal Point
of View

• I. Instantaneous Studies - Surveys
• II. Longitudinal Studies
• A. Retrospective Studies
• Historical Observational Cohort
• Case - Control
• B. Prospective Studies
• Prospective Observational Cohort
• Clinical Trial
• C. Hybrid Designs

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A Schematic for Temporal Classification
Prospective
Retrospective
Observational Cohort
Observational Cohort
Randomization
Clinical Trial
Case - Control
Now
Instantaneous Survey
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I. InstantaneousPopulation-Based Studies

• Synonyms
• Survey
• Population-Correlation Study
• Ecological Study
• Two or more populations are instantaneously
  compared through the prevalences of both exposure
  and disease.
• As summarized units get smaller (country ? region
  ? neighborhood ? individual), a survey
  approaches a historical observational cohort
  study.

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Population-Based Studies

• Advantages
• Instantaneous.
• Easy access to a large and varied population.
• Good for hypothesis generation.

• Disadvantages
• Intervention is usually not feasible.
• Very little information on causality IARC
  standards require individual-based evidence.

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II. LongitudinalIndividual-Based Studies

• A longitudinal study observes exposures and
  events for individuals over a period of time.
• There are two types, depending on whether one is
  looking forwards (prospective) or backwards
  (retrospective) from the present.

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Longitudinal StudiesA. Retrospective

• Historical Observational Cohort
• Synonyms - survey, retrospective cohort study.
• Examines outcomes among patients with past
  exposures.
• E.g., track down 1950s asbestos miners
  determine current status.
• Case - Control (Breslow and Day, 1980)
• Synonyms - case referent, retrospective study.
• Examines past exposures among a group of patients
  with current outcomes.
• E.g., interview mesothelioma patients determine
  past exposures.

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Historical Observational Cohort Studies

• Advantages
• Quick results - no wait.
• Easy to get large samples by mining databases.
• Yields wide range of sequelae.
• Useful for investigating rare treatments or
  exposures.

• Disadvantages
• No opportunity to customize data collection.
• No possibility for blinding.
• Many possible biases
• Confounding
• Selection
• Information

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Case - Control Studies

• Disadvantages
• Gives narrow picture of risks due to treatment or
  exposure.
• Biases
• Confounding
• Selection
• Recall
• Yields only estimates of relative, not absolute
  risk.

• Advantages
• Cheap, quick - record searching can be automated.
• Useful for pilot studies.
• Useful for investigating rare disorders.

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Hypothetical Historical Cohort Study

• Exposed Group
• 100 Patients
• 10 Events
• Rate .1
• Odds Ratio ??2

• Control Group
• 100 Patients
• 5 Events
• Rate .05

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Hypothetical Case-Control Study

• Event Group
• 100 Patients
• 10 Exposures
• Event Rate per Exposure
  ?
• (Not 100/200).

• Non-Event (Control) Group
• 100 Patients
• 5 Exposures
• Odds Ratio ??2

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Longitudinal StudiesB. Prospective

• General Advantages
• Can collect detailed exposure, treatment,
  disease, and demographic information.
• Blinding is possible.
• Recall and information bias may be eliminated.
• Useful for investigating rare treatments or
  exposures.
• Classification depends on the presence of
  intervention.

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Prospective Studies

• Prospective Observational Cohort
• Synonyms - prospective trial, clinical trial.
• No intervention.
• Randomized Controlled Clinical Trial
• Synonyms - prospective interventional cohort
  study, experiment, prospective trial, clinical
  trial.
• Experimenters directly intervene in patient
  treatment, usually on a randomized basis with
  controls.

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Prospective Observational Cohort Study

• Additional
• Advantage
• Passive observation no need to dictate
  treatment.

• Disadvantages
• May take a long time to accrue cases and wait for
  results.
• Potential confounding bias due to lack of
  randomization and suitable controls.

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Clinical Trials

• Additional Advantages
• The most definitive tool for evaluation of the
  applicability of clinical research - 1979 NIH
  release.
• Biases may be eliminated.
• Good design may make analysis simple.

• Disadvantages
• As above, may take a long time.
• Must be ethically and laboriously conducted.
• Requires treatment on basis (in part) of
  scientific rather than medical factors. Patients
  may make some sacrifice (Meier, 1982).

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Phases of a Clinical Trial

• Biochemical and pharmacological research.
• Animal Studies (Gart, 1986 Schneiderman, 1967).
  
• Phase I (Storer, 1989) - estimate toxicity rates
  using few ( 10 - 40) healthy or sick subjects.
• Phase II (Thall Simon, 1995) - determines
  whether a therapy has potential using a few very
  sick patients.

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Phases of a Clinical Trial (cont.)

• Phase III - large randomized controlled, possibly
  blinded, experiments
• Phase IV - a controlled trial of an approved
  treatment with long-term followup of safety and
  efficacy.

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Longitudinal StudiesC. Hybrid Designs

• Prospective Treatment, Historical Controls
• Currently treated series of patients is compared
  with a previous series.
• See Gehan Freireich (1974), Gehan (1984).
• Advantages
• Doesnt assign treatments.
• No need to recruit controls.

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Longitudinal StudiesC. Hybrid Designs (cont.)

• Prospective Treatment, Historical Controls
• Disadvantages
• Same as in Historical Observational Cohort
  except that characteristics of treated patients
  (only) can be collected.
• Selection bias likely because of time lag between
  groups.

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Hybrid Designs

• Prospective Treatment with Both Prospective and
  Historical Controls
• Uses both types of controls to maximize
  efficiency and minimize bias
• See Pocock (1976a and 1976b).

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Bias in Clinical Studies

• Definition Bias is a systematic error in
  estimation which is not reduced by increasing the
  study sample size (as opposed to random
  variation).
• See Sacket (1979) and other articles in the same
  issue Rose (1982) and Lachin (1988).
• Classification is based on whether bias occurs at
  the time of patient Selection or at the time of
  Information collection or at the time of
  Publication.
• They are all variants of Confounding, in which a
  third variable is related to both treatment and
  outcome.

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I. Selection Bias

• Prevalence - Incidence Bias
• Prevalence (observed occurrence) of a trait ??
  Incidence (rate of onset).
• Cause gap between exposure, selection of
  subjects.
• Not a problem with irreversible events such as
  mortality, if detectable.
• E.g., hypertension may disappear with onset of CV
  disease and can be overlooked as a risk factor.
• See Neyman, 1955.
• (Any retrospective study, especially
  case-control.)

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Selection Bias

• Admission Rate Bias
• Patients may differ from noninstitutionalized
  subjects in size or direction of effects.
• E.g., systemic weakness vs. arthritis
• Negative relation among inpatients
• Positive relation among outpatients.
• See Berkson, 1946.
• (Any nonrandomized study with a mix of patient
  sources, especially case-control.)

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Selection Bias

• Nonrespondant (Volunteer) Bias
• Nonparticipation may be related to the subject of
  investigation.
• E.g., smokers ignore surveys more often than do
  non-smokers (Seltzer, 1974).
• For general methods to analyze data with
  nonignorable nonresponse see Little and Rubin
  (1987) and Rubin (1987).
• (Case-control, though drop-outs can effect any
  study not analyzed intent to treat.)

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Example Where to add armor to fighter planes?

• In World War II, the U.S. Air Force conducted an
  investigation into where armor could most
  effectively be added to fighter planes.
• Researchers examined returning aircraft, mapped
  the locations of bullet holes, and recommended
  that the most commonly pierced areas be
  reinforced.
• Their recommendation neglected the most vital
  part of the aircraft, which was intact in all
  returning aircraft the area surrounding the
  pilots head!

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II. Information Bias

• Detection Signal (Diagnostic Suspicion) Bias
• In unblinded studies, an exposure may be
  considered a risk factor for an endpoint, and
  such patients preferentially observed.
• In blinded studies, an exposure may make an
  endpoint more detectable.
• E.g., estrogen causes bleeding from uterine
  cancer to be more easily detectable.
• (Any unblinded study except case-control also
  clinical trials with sensitive endpoints.)

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Reports of Original Studies JAVMA 191, 12/1/87
High-rise syndrome in cats Wayne O. Whitney,
DVM Cheryl J. Mehlhaff, DVM
Selection and/or detection bias
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Information Bias

• Exposure Suspicion Bias
• An outcome may cause the investigator to look for
  a particular exposure.
• The temporal reverse of detection signal bias.
• E.g., arthritis and knuckle-cracking.
• (Case-control studies.)

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Information Bias

• Recall (family information) Bias
• Similar to exposure suspicion bias, but errors
  originate with the subject or his/her family.
• E.g., in a study of prescription use among women
  with fetal malformation, 28 reported
  unverifiable exposure vs. 20 of the controls
  (Klemetti Saxen, 1967).
• (Case-control studies.)

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III. Publication (Reporting) Bias

• Even a perfect study leads to bias if
  dissemination depends on the direction of its
  result.
• Causes
• Commercial reasons
• Researchers personal motivations
• Editorial Policy !
• Vickers, et al. (1998) show that the problem is
  widespread in some countries, 100 of
  publications show treatment effects.

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Publication (Reporting) Bias

• A version of the multiple comparisons problem
  (Miller, 1985), or testing to a foregone
  conclusion.
• E.g., ORG-2766 protected nerves from cytotoxic
  injury in 55 women with ovarian cancer - NEJM
  lead article (van der Hoop, et al., 1990) a
  subsequent negative study of 133 women - ASCO
  Proceedings abstract (Neijt, et al., 1994).
• (All Studies.)

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A type of reporting bias Multiple Comparisons
(Data Dredging)

• A p-value is interpreted as the probability of
  attaining a result as extreme that observed given
  that the result is false (under the null
  hypothesis) it can be viewed as the false
  positive rate under the null hypothesis.
• This assumes that only a single test is
  conducted. If many tests are performed, it is
  possible to sample to a foregone conclusion and
  produce a falsely low p-value.
• For example, if twenty-five independent tests are
  conducted, the probability of at least one
  p-value being less than .01 is .22.
• Often only the significant result is reported,
  and the 24 others ignored.

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IV. Confounding (General)

• Caused by any situation in which
• A third variable exists which isnt known or at
  least isnt accounted for
• It is associated with the cause
• and
• It is also associated with the effect.
• Then
• The supposed cause-effect relation will be
  confounded by the third variable.
• (Any nonrandomized study)

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Do Storks Bring Babies?
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Population of Oldenburg, Germany,
1930-1936 (Ornithologische Monatsberichte 44,
Jahrgang, 1936, Berlin)
Humans (1000s)
Storks (1000s)
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References

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• Breslow, N.E. and Day, N.E. (1980). Statistical
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• Miller, R. Publication bias (1985). Entry in
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