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Bias in observational study designs: Prospective cohort studies

Article in The BMJ · December 2014

DOI: 10.1136/bmj.g7731 · Source: PubMed

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BMJ 2014;349:g7731 doi: 10.1136/bmj.g7731 (Published 19 December 2014)
Endgames
STATISTICAL QUESTION
Bias in observational study designs: prospective
cohort studies
Philip Sedgwick reader in medical statistics and medical education
Institute for Medical and Biomedical Education, St George’s, University of London, London, UK
The Women’s Health Initiative Observational Study, a
prospective cohort study, was designed to investigate causes of
morbidity and mortality in postmenopausal women. In total, 93
676 women aged 50-79 years were recruited at 40 clinical
centres throughout the United States between 1993 and 1998.
Women were not recruited if they had conditions that were
predictive of survival less than three years or had complicating
conditions such as alcoholism, drug dependency, or dementia.
Researchers used the data collected for this study to investigate
the association between smoking and the risk of invasive breast
cancer. For this analysis, 13 686 women from the original cohort
were excluded, including 12 075 with a history of cancer (except
non-melanoma skin cancer) at baseline and 1168 whose smoking
status was missing. In addition, 443 women were lost to
follow-up. The size of the remaining cohort for analysis was 79
990.1
The primary outcome was pathologically diagnosed invasive
breast cancer. Smoking behaviour had been assessed at baseline
using self reported measures of lifetime passive and active
smoking exposure. Information on other risk factors as potential
confounders had also been collected at baseline, including age,
ethnicity, body mass index, physical activity, and alcohol intake.
The women were followed prospectively until 14 August 2009,
or until they were diagnosed with invasive breast cancer,
whichever came first. The average length of follow-up was 10.3
years. In total, 3520 incident cases of invasive breast cancer
were identified. Compared with women who had never smoked,
the risk of breast cancer was significantly higher in former
smokers (adjusted hazard ratio 1.09, 95% CI 1.02 to 1.17) and
in current smokers (1.16, 1.00 to 1.34). Among women who
had never smoked, those with the most extensive exposure to
passive smoking had a significantly increased risk of breast
cancer compared with those who had never been exposed to
passive smoking (1.32, 1.04 to 1.67). The researchers concluded
that active smoking was associated with an increase in breast
cancer risk in postmenopausal women. An association between
passive smoking and increased risk of breast cancer was also
suggested.
p.sedgwick@sgul.ac.uk
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Page 1 of 3
ENDGAMES
Which of the following, if any, might the above cohort study
and its results have been prone to?
a) Allocation bias
b) Attrition bias
c) Confounding
d) Healthy entrant effect
e) Response bias
f) Selection bias
Answers
Answers b, c, d, e, and f are true, whereas a is false.
A prospective cohort study was used to investigate the
association between smoking behaviour and diagnosed invasive
breast cancer in postmenopausal women. Prospective cohort
studies are observational by design and have been described in
a previous question.2 The participants were postmenopausal
women originally recruited to the Women’s Health Initiative
Observational Study, which had been designed to investigate
causes of morbidity and mortality. Cohort studies are prone to
various types of bias. Bias is a systematic error, rather than
random variation or lack of precision, in the recruitment of
participants, the measurement of their risk factors and outcomes,
or reporting of the results. Observational studies are recognised
to be prone to three broad types of bias, including selection bias,
information bias, and confounding. The most common types of
bias within these categories are described below.
The Women’s Health Initiative Observational Study originally
recruited 93 676 women aged 50-79 from 40 clinical centres
throughout the US between 1993 and 1998. The cohort would
probably have been representative of the population of
postmenopausal women in its characteristics because it was
sampled from a large number of clinical centres. However, the
cohort was still prone to selection bias (f is true), a general term
used to describe a group of biases and effects that result in a
sample that is not representative of the population from which
it was selected. Selection bias results in a lack of external
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BMJ 2014;349:g7731 doi: 10.1136/bmj.g7731 (Published 19 December 2014)
validity—that is, the extent to which the study results can be
generalised to the population that the sample is meant to
represent. Selection bias includes non-response bias, the healthy
entrant effect, and attrition bias, which are all described below.
Non-response bias would have occurred if the women who
accepted the invitation to be part of the study were different
from those who did not. However, any differences in
characteristics (including demographics, risk factors such as
smoking behaviour, and prognostic factors) would be difficult
to quantify because limited information, if any, would be
available for those who refused to be part of the cohort.
Non-response bias should not be confused with response bias,
described below.
In total, 93 676 women were recruited to the Women’s Health
Initiative Observational Study. Women were not recruited if
they had conditions that were predictive of survival less than
three years or had complicating conditions such as alcoholism,
drug dependency, or dementia. For the above analysis, 12 075
(12.9%) women with a history of cancer (except non-melanoma
skin cancer) were excluded at baseline. When investigating the
epidemiology of invasive breast cancer, it was important that
the women selected were healthy and free of cancer at baseline.
This enabled the temporal association between the risk factor
of smoking behaviour and diagnosis of invasive breast cancer
to be determined. In particular, it ensured that smoking
behaviour and exposure to other pertinent risk factors occurred
before the diagnosis of invasive breast cancer, thereby permitting
a potential causal role to be investigated. Because women were
healthy and free of cancer at baseline, the cohort would have
been healthier than the general population of postmenopausal
women. The results of the study would therefore have been
prone to the healthy entrant effect (d is true)—a reduction in
rates of morbidity and mortality in the initial stages of the study
compared with the general population of postmenopausal
women. Rates of morbidity and mortality would have started
to increase and resemble those in the population several years
after the start of the study.
As is typical of most cohort studies, the Women’s Health
Initiative Observational Study recruited a large number of
women who were followed for a substantial period of time. The
median length of follow-up in the above study was 10.3 years.
This ensured that a sufficient number of women received a
diagnosis of invasive breast cancer, thereby enabling the
association with smoking to be investigated. It would have been
difficult to maintain contact with all of the women because of
the size of the cohort and length of follow-up. Of the 93 676
women originally recruited to the Women’s Health Initiative
Observational Study, 443 (0.5%) were lost to follow-up.
Therefore, the above study was prone to attrition bias (b is true),
also known as loss to follow-up bias. Attrition bias would have
occurred if the women lost to follow-up differed in a systematic
way to those not lost to follow-up. In particular, it would have
been a problem if the reason for loss to follow-up was related
to the risk factor of smoking or the outcome of diagnosed
invasive breast cancer. Although the proportion of the cohort
in the above study that was lost to follow-up was minimal, it
may still have biased the results. There is no exact proportion
of a cohort that when lost to follow-up results in attrition related
bias becoming a concern.
Of the original cohort of 93 676 women, 1168 (1.25%) had
missing values of smoking status at baseline. If the participants
with complete data on smoking behaviour at baseline were not
representative of the population of postmenopausal women,
then the women with missing data would have introduced
selection bias.
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Page 2 of 3
ENDGAMES
The collection of data in the above study was prone to
information bias, a type of bias that occurs during data
collection. It would have occurred if the measurements of the
risk factors (including smoking) or outcome (diagnosed invasive
breast cancer) were systematically distorted. Such bias in data
collection can be unconscious or otherwise and can come from
the investigators or participants. Response bias would have
occurred on behalf of the women if their reported smoking
behaviour was systematically different from their actual smoking
behaviour (e is true). For example, women may have
under-reported their smoking behaviour because they were
aware that it can affect their health. Assessment bias, also known
as observer bias, would have occurred if the outcome of invasive
breast cancer was diagnosed incorrectly. For example, diagnosis
could have been influenced by knowledge of the study research
hypotheses. Response and assessment biases are part of a group
of biases collectively known as ascertainment bias, sometimes
referred to as detection bias.
Confounding would have occurred if a variable, such as alcohol
intake, obscured the association between smoking behaviour
and diagnosed invasive breast cancer. Alcohol intake would
then be a confounding variable or confounder. To be a
confounder, alcohol intake would have to be a risk factor for
diagnosed invasive breast cancer. Alcohol intake would also
have to be associated with smoking behaviour. For example, if
women who smoked were also more likely to drink alcohol, the
increased risk of invasive breast cancer associated with being
a current smoker might have partly been the result of alcohol
intake. Confounding was accounted for at the analysis
stage—the association between smoking and diagnosed invasive
breast cancer (as measured by a hazard ratio) was adjusted for
all other potential confounders measured at baseline. The
adjusted hazard ratio provided a true indication of the association
between smoking behaviour and diagnosed invasive breast
cancer, with all other confounding variables being equal.
The results of the above study were still prone to confounding
(c is true), however, because it was unlikely that all potential
confounders were measured and adjusted for. Furthermore,
confounding variables must be measured accurately. In the
above study, information on smoking behaviour and other
potential confounders was collected at baseline. However, if
cohort members changed their smoking behaviour during
follow-up and after baseline measurements, perhaps as a result
of knowledge of the study research hypotheses, this would have
introduced further confounding.
Allocation bias is mainly of concern in clinical trials, not cohort
studies (a is false). It occurs when there is a systematic
difference between participants in how they are allocated to
treatment groups. For example, researchers may allocate people
who they think would show the greatest benefit to a particular
intervention, perhaps because they favour the intervention and
wish to show that it is more effective than the control treatment.
Allocation bias is eliminated by randomising trial participants
to treatment so that all participants have the same probability
of being allocated to each treatment group.3
Competing interests: None declared.
1 Luo J, Margolis KL, Wactawski-Wende J, Horn K, Messina C, Stefanick ML, et al.
Association of active and passive smoking with risk of breast cancer among
postmenopausal women: a prospective cohort study. BMJ 2011;342:d1016.
2 Sedgwick P. Prospective cohort studies: advantages and disadvantages. BMJ
2013;347:f6726.
3 Sedgwick P. Why randomise in clinical trials? BMJ 2012;345:e5584.
Cite this as: BMJ 2014;349:g7731
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 BMJ 2014;349:g7731 doi: 10.1136/bmj.g7731 (Published 19 December 2014) Page 3 of 3

ENDGAMES

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