Selection bias resulting from the requirement for prior consent
in observational research: a community cohort of people with
ischaemic heart disease
Brian Buckley, Andrew W Murphy, Molly Byrne, Liam Glynn
............................................................... ............................................................... .....
See end of article for
B Buckley, Department of
General Practice, National
University of Ireland,
Accepted 23 January 2007
Published Online First
13 May 2007
Heart 2007;93:1116–1120. doi: 10.1136/hrt.2006.111591
Objective: To evaluate differences between adults who consent to participate in observational research and
those who do not.
Design: Prospective, population-based cohort study.
Setting: 35 randomised Irish general practices.
Participants: 1609 adults with ischaemic heart disease identified in 2000–1.
Intervention: Medical records search, postal questionnaire and consent form in 2005–6.
Main outcome measures: Differences in demographic and prognostic risk factors between consenters and
Results: At follow-up, charts were located for 1592 patients (98.9%). Questionnaires were sent to 1269
patients and 876 were returned (69%). Of these, 574 (65.5%) gave consent for participation in further
research. Logistic regression identified four characteristics as independently positively predictive of consent to
participation in further research among questionnaire responders: having undergone percutaneous
transluminal coronary angioplasty was associated with an increased odds of consent, with an odds ratio
(OR) of 1.77 (95% CI 1.09 to 2.86), as was a last recorded blood pressure ,140/90 mm Hg (OR=1.45
(1.00 to 2.09)), a last recorded total cholesterol level ,5 mmol/l (OR=1.71 (1.16 to 2.54)) and being an ex-
smoker rather than a current smoker or non-smoker (OR=1.73 (1.17 to 2.57)).
Conclusions: This research demonstrates the potential impact of consent bias in observational research on
ischaemic heart disease, a disease of everyday clinical importance in Europe. It demonstrates that clinically
important prognostic variables may be associated with consent preferences. Future cohorts, dependent upon
prior written consent, may contain disproportionate numbers of those who have made healthy lifestyle
decisions, have previously benefited from treatment or whose clinical risk factors are already well managed.
As a result, the generalisability of such research may be diminished and the effects of treatments over- or
required almost universally where identifiable data are sought
for research purposes.1–6
The implications for research of the requirement for prior
written consent have been widely discussed, but the debate
‘‘has largely been confined to professional circles’’.7–10Research
evidence considering public attitudes towards the use of
personal medical information in research is limited.1 7 9
Although the Medical Research Council reported that the use
of personal data in publicly funded health research is viewed
positively by the public ‘‘if it will advance medical practice’’,
and research in Leicestershire reported patients’ ‘‘altruistic
views about participation in research’’,1 11a number of other
studies have found that the public would prefer their consent to
granted.9 12 13Research also suggests that there may be only
limited understanding among the public of what information is
contained in medical records and of the value of such data to
research.1 11 13The promotion of greater understanding appears
worthwhile: a study on attitudes to the retention and research
use of tissue samples has demonstrated a striking increase in
the proportion of patients willing to consent to the use of their
personal data in research when the potential value of their
doing so was explained.14
n recent years patients’ rights to privacy and confidentiality
have been increasingly acknowledged both in law and by
research ethics committees. Patients’ prior written consent is
The threat posed to observational research by current
requirements for prior written consent is grave. Concerns have
been expressed among researchers that there is a danger that
constraints may have become too strict: that in order to prevent
limited and largely theoretical harm to people, work may be
prevented which offers large benefits to society.7 13 15–20
Among the most serious consequences of the requirement for
prior written consent is the threat to the validity of observa-
tional research posed by ‘‘consent bias’’, a term coined to
describe the selection bias resulting from the loss of non-
consenters to any cohort. It has been suggested that ‘‘patients,
the public and professional organisations must consider the
implications … before epidemiology and health services
research are regarded as too biased to rely on.’’15
However, demonstrating the potential seriousness of this
phenomenon has only been possible in a small number of
studies with access to data for non-consenters as well as
consenters. In Rochester, Minnesota, Jacobsen et al found in
their medical records research—to which 79% consented—that
those refusing consent were more likely to be female and
younger than 60 years. Those with ‘‘sensitive’’ diagnoses such
Abbreviations: AMI, acute myocardial infarction; BMI, body mass index;
CABG, cardiac artery bypass grafting; GMS, General Medical Services;
GP, general practitioner; IHD, ischaemic heart disease; OR, odds ratio;
PTCA, percutaneous transluminal coronary angioplasty
as reproductive disorders, mental disorders or infectious
diseases were also less likely to consent to participation.18A
study based on the Registry of the Canadian Stroke Network
supported the American finding that women were more likely
to refuse consent than men but found that those who did not
consent to interview and medical records review (49%) were
more likely to be older. In the UK, Angus et al found that
different proportions of men and women consented to research
participation in different age groups and that consenters were
less likely to live in deprived areas.21Al-Shahi et al demon-
strated that clinically important prognostic variables can be
vulnerable to consent bias: among a cohort of people with
intracranial vascular malformation, the positive association
between one prognostic variable—which often influences the
decision to treat in clinical practice—and an important outcome
was confirmed when data relating to their whole cohort were
analysed, but not so when those who did not give consent
(41%) were excluded.15
The CoHeart study
The CoHeart study is a 5-year follow-up of a representative
cohort of 1609 people with established ischaemic heart disease
(IHD) in 35 randomised and stratified general practices in the
west and northwest of Ireland.22The cohort was established in a
cross-sectional study in 2000–1 and presented a valuable
opportunity to conduct a follow-up study of the secondary
prevention of IHD among a representative community cohort at
a time when the future of such observational work is at risk.
IHD was defined as a history of previous acute myocardial
infarction (AMI), angina pectoris, cardiac artery bypass grafting
(CABG) or percutaneous transluminal coronary angioplasty
(PTCA). With original data available for cohort members
irrespective of their consent preferences for research participa-
tion, the study also presented an opportunity to test hypotheses
relating to consent bias among a large community-based cohort
of people with established IHD.
Ethical approval for the study
Ethical approval for both baseline and follow-up studies was
granted by the Irish College of General Practitioners. Ethical
approval at baseline allowed researchers to identify the practice
populations of people with IHD through review of general
practice records, to establish practice IHD registers, to collect
medical and demographic data and to send each member of the
cohort a patient questionnaire. The baseline database was
subsequently anonymised. Follow-up data collection was
dependent upon the consent and participation of the individual
general practitioners (GPs), who are the legal data controllers
of patient records in Ireland. Ethical approval allowed for
collection of anonymous data from patient records, linked in
the practices to baseline data by unique patient identification
codes. A protocol was established which enabled the sending of
patient questionnaires by agents of the practices without the
need to disclose patients’ identities to follow-up researchers. To
facilitate future follow-up, a consent form was enclosed with
the patient questionnaire which requested patients’ written
consent and identification for involvement in further research.
Analysis of consent bias
Patient questionnaires could be returned with or without the
consent form—or not returned at all. Thus the study identified
three subgroups of patients with different consent preferences:
‘‘consenting responders’’ (who completed the questionnaire
and gave their consent and contact details for participation in
further research), ‘‘non-consenting responders’’ (who com-
pleted the questionnaire but did not consent) and ‘‘non-
These subgroups represented different preferences relating to
participation in research and consent for access to personal
medical data and thus afforded an opportunity to consider
associations between these preferences and demographic,
medical and healthcare data.
The selection of variables considered in this study was informed
by sources of consent bias identified in the literature: age (by
10-year age bands), sex, socioeconomic status (measured by
eligibility or ineligibility for free General Medical Services
(GMS) within the Irish health system—at the time of the
follow-up study just under 40% of the population in the area in
which the study was based were GMS eligible, representing the
least affluent members of society), and prognostic risk factors.
Prognostic risk factors for subsequent IHD events which were
considered in analysis were previous AMI, previous CABG or
previous PTCA (whether or not patients had ever experienced
these events), blood pressure and cholesterol management (last
reading at follow-up less than or equal to or greater than the
level recommended by the Second Joint Task Force of the
European and other Societies on Coronary Prevention23 24),
body mass index (BMI; (25 kg/m2or .25 kg/m2), self-
reported smoking status (current, ex- or non-smoker at
follow-up) and exercise behaviour (less than or equal to or
greater than the level recommended by the Second Joint Task
Questionnaire at follow-up25).
Univariate analysis used to consider associations between
demographic and clinical risk factor variables were x2(for sex,
socioeconomic status, IHD status, blood pressure and choles-
terol management, BMI, smoking status and exercise beha-
viour) and x2for trend (for age). Multiple logistic regression
was subsequently used to determine which variables indepen-
dently predicted questionnaire response and consent preference
when the effect of other variables was taken into account.
Those who had died since baseline and those who were
excluded from receipt of the patient questionnaire and consent
form were excluded from analyses.
Baseline chart data were available for 1609 patients: 65.4%
(n=1053) male and 34.6% female (n=556); mean (SD) age
was 66 (9.1); 79% were GMS eligible. Patients could be
Follow-up data collection flow chart.
Selection bias in ischaemic heart disease 1117
excluded from receipt of the baseline patient questionnaire by
their GPs for reasons such as very poor health status or
illiteracy. Baseline patient questionnaires were sent to 1577
patients and returned by 1084 (response rate 68.7%).
At follow-up, records were located for 1592 patients (98.9%).
The mean (SD) age of the surviving cohort was 69.5 (9.2).
Patients could be excluded from receipt of the patient
questionnaire at follow-up for reasons such as death since
baseline, serious illness, having moved away from the practice,
illiteracy: 340 patients (including all of those for whom no
records could be located) were excluded by their GPs for these
reasons as outlined in fig 1. Questionnaires were sent to the
remaining 1269 patients and were returned by 876 (response
rate 69%). Of responders, 574 (65.5%) completed and signed
the form which gave consent for participation in further
Responders and non-responders: demographics and
The levels of non-response were almost identical between the
sexes, with 30.9% of women and 31.0% of men not responding
at all. Univariate analysis identified a significant association
between response and cholesterol management: of patients
whose last serum cholesterol reading was under the recom-
mended 5 mmol/l, 71.8% (n=522) returned the completed
questionnaire compared with 66% (n=285) of those whose
readings were above this level (x2=4.4; df=1; p,0.05).
However, logistic multiple regression identified no variable as
independently predictive of questionnaire response.
Consenters and non-consenters: demographics and risk
Among responders univariate analysis detected no significant
association between consent preferences and either age or
socioeconomic status. Neither was any significant association
between consent preference and blood pressure management,
previous AMI, BMI or exercise behaviour identified. Gender
was found to be significantly associated with consent pre-
ference, with 68.1% of men (n=388) compared with 60.8% of
women (n=186) consenting to participation in further
research (x2=4.7; df=1; p,0.05). Of those whose last serum
cholesterol reading was below the recommended 5 mmol/l,
69.2% (n=361) consented to further participation compared
with 61.4% (n=175) of those whose reading was above this
level (x2=5; df=1; p,0.05). Having had surgical cardiac
interventions was found to be significantly associated with
consent, with 72.5% (n=150) of those who had had a previous
CABG compared with 64% (n=419) of those who had not
consenting (x2=5.1; df=1; p,0.05) and 74.2% (n=138) of
those who had had PTCA consenting compared with 63.5%
(n=427) of those who had not (x2=7.5; df=1; p,0.01).
Smoking status was associated with consent, with smoking
cessation in particular influencing consent preferences: 73.4%
(n=312) of ex-smokers consented to participation compared
with 61.4% (n=62) of smokers and 61.6% (n=162) of non-
smokers (x2=13.2; df=3; p,0.01).
To evaluate how IHD risk factor variables predicted consent
preferences after controlling for other variables, a logistic
multiple regression model was fitted to the 540 cases for whom
complete data were available, summarised in table 1.
Although the explained variation was relatively small,
analysis identified four characteristics as independently and
significantly positively predictive of consent to further research
participation when the effect of other predictors was taken into
account: having undergone PTCA, with an odds ratio (OR) of
1.77 (1.09 to 2.86); previous smoking cessation (that is to say
being an ex-smoker rather than a current smoker or non-
smoker), with an OR of 1.73 (1.17 to 2.57); a last recorded
blood pressure within recommended levels (,140/90 mm Hg),
OR=1.45 (1.00 to 2.09); and a last recorded total cholesterol
level within recommended levels (,5 mmol/l), OR=1.71 (1.16
to 2.54). Associations were considered among all responders
between the variables identified as predictors of consent
preference: smoking cessation was significantly associated with
PTCA (x2=19.8; df=1; p,0.01).
The cases included in the analysis represented 61.6% of
responders. The loss of 38.4% resulted for the most part from
incomplete patient questionnaire data, most notably failure to
supply either height or weight, so that BMI could not be
calculated. No significant difference in demographic or clinical
characteristics was identified between those included and those
demonstrates thepotential for increasing consent requirements to
create selection biases which might undermine observational
research. The study has benefited from having access to a large
logistic regression (n=540)
Risk factors as predictors of consent to further participation in research: summary of
Risk factors No (% of total) Odds ratio (95% CI)
Last BP ,140/90 mm Hg
Last total cholesterol ,5 mmol/l
BMI .25 kg/m2
1.13 (0.74 to 1.72)
1.000 (0.99 to 1.00)
0.99 (0.64 to 1.54)
0.86 (0.59 to 1.26)
0.98 (0.62 to 1.53)
1.77 (1.09 to 2.86)*
1.45 (1.00 to 2.09)*
1.71 (1.16 to 2.54)**
1.73 (1.17 to 2.57)**
0.95 (0.80 to 1.12)
1.00 (0.99 to 1.01)
Cox and Snell R2=0.056; Nagelkerke R2=0.078
AMI, acute myocardial infarction; BMI, body mass index; BP, blood pressure; GMS, General Medical Services; CABG,
cardiac artery bypass grafting; PTCA, percutaneous transluminal coronary angioplasty.
1118Buckley, Murphy, Byrne, et al
community-based cohort for whom a rich database based on
medical records review and patient questionnaire was available at
both baseline and the 5-year follow-up. The request for patient’s
contact details and consent for participation in research was
included with patient questionnaires to facilitate subsequent
follow-up, but also afforded the opportunity to consider consent
and research participation preferences amongst a large represen-
tative cohort of people with IHD.
This study’s main finding is that consent bias threatens the
validity of future observational research among people with
IHD. In this respect, the research supports the findings already
published on consent bias. Like Al-Shahi et al, this research
demonstrates that clinically important prognostic variables can
be associated with consent preferences, and this has serious
implications for future research. However, this study extends
these implications from the disease area in the previous
research—which is potentially catastrophic but relatively
rare—to one which is of everyday clinical importance in
The size of the cohort in this study allowed sufficient power
to conduct multivariate analysis. Unlike existing published
results, this research found that although gender was identified
as significantly associated with consent preferences by uni-
variate analysis, this was not the case when other predictors
were controlled for.
However, the association between clinically important prog-
nostic variables and consent preferences was shown to be
significant: patients who had stopped smoking, whose choles-
terol and blood pressure were well managed or who had
previously benefited from PTCA were more likely to consent to
participation in research. Previous PTCA was shown to be
associated with smoking cessation. Although it seems likely
that the former drives the latter, this cannot be determined
from the data; if so, then it might be concluded that it is the
healthy lifestyle decision (smoking cessation) rather than the
medical intervention which is the true predictor of consent to
The implication is that if cohorts in the future are dependent
upon prior written consent they are likely to contain
disproportionate numbers of those who have made healthy
lifestyle decisions, who have previously benefited from health-
care or those whose clinical risk factors are already well
managed. This may have two serious consequences: first, the
generalisability of observational research will be reduced;
second, the effects of treatments may be variously over-
estimated or underestimated if those who are most unwell or
are not making healthy lifestyle decisions are under-repre-
sented in study populations.
All the stakeholders in healthcare research, including the
public, need to understand and deal with the serious implica-
tions for research—and ultimately for medicine—of over-
zealous interpretation and implementation of confidentiality
laws and guidance. The directive approved by the European
Parliament which prompted the introduction of new national
data protection legislation permitted member states to make
exceptions in the case of health-related research where the
benefits to society outweigh any harm attributable to the
invasion of privacy.26In some countries these provisions were
not incorporated in legislation so that some forms of observa-
tional research have become nearly impossible. In others—such
as the UK—the use of identifiable data without prior consent in
medical research is permitted in law under certain circum-
stances. But the associated laws and bureaucracy are complex
and public attitudes towards the use of personal medical
information in research are unclear. As a result, the require-
ment for prior consent has emerged as a default position of
safety amongst regulatory bodies and research ethics commit-
If the effectiveness of observational research, of epidemiology
and, ultimately, of some elements of medicine are not to be
diminished, every effort must be made to ensure that the
provisions made available to health-related research by the
European Parliament are adopted and implemented where this
is not already the case.
We particularly acknowledge the help of the Health Research Board,
Noel Scott and Diarmuid O’Donovan of the HSE (Western area) and the
practice staff and participating general practitioners: Drs Marcus Allen;
Desmond Bluett; Charles Bourke; Sean Bourke; Martin Brennan; Vivian
Brennan; James Brogan; Marian Brogan; Declan Clinton; Seamus
Cryan; Martin Daly; Anthony Delap; John-Mark Dick; Ken Egan; Noel
Farrell; Mary Feerick; Brendan Forkan; Margaret Gilligan; Enda
Harhen; Edward Harty; Richard Joyce; Ciaran Kelly; Bernard
McGuire; Pauric Mitchell; Paul Money; Kay Moran; Daniel Murphy;
Kieran O’Reilly; John O’Sullivan; Roddy Quinn; John Regan; Michael
Regan; Eamonn Shea; John Sheerin; Richard Tobin; David Townley;
Kieran Whyte. One GP asked to remain anonymous.
Brian Buckley, Andrew W Murphy, Liam Glynn, Department of General
Practice, National University of Ireland, Galway, Ireland
Molly Byrne, Department of Psychology, National University of Ireland,
Funding: Baseline and follow-up studies were both funded by the Health
Research Board, Dublin and the Health Services Executive (Western Area).
Conflict of interest: None.
What this paper adds
N The potential impact of consent bias is demonstrated
among a large European community-dwelling cohort of
people with ischaemic heart disease, a disease of
everyday clinical importance.
N In future, observational research consent bias may mean
that determination of the effects of treatments becomes
N The potential of consent bias to effect the validation of
clinically important prognostic predictors is demonstrated
in a sample large enough to allow control of other
What is known on this subject
N There is worrying but limited evidence that requiring
prior written consent may affect the validity of observa-
N Those with ‘‘sensitive’’ conditions are less likely to consent
to the use of their medical data.
N In the relatively rare context of intracranial vascular
malformation, it has been shown that the requirement for
prior consent could affect a study’s ability to identify the
prognostic importance of a factor which in clinical
practice often influences the decision to treat.
Selection bias in ischaemic heart disease 1119
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IMAGES IN CARDIOLOGY ............................................................... .................
Intracardiac echocardiography in the diagnosis of prosthetic valve endocarditis
spine fracture. She had undergone coron-
ary artery bypass grafting and bioprosthetic
aortic valve replacement 3 years before this
admission. On presentation, shewas febrile
with blood cultures positive for Candida
parapsilosis. Serial transthoracic echocardio-
grams did not show valvular vegetations,
and transoesophageal echo was considered
relatively contraindicated owing to the
patient’s cervical injury. Despite treatment
with intravenous fluconazole and caspo-
fungin, fever and positive repeat blood
cultures persisted. A definitive diagnosis
was made by intracardiac echocardiogra-
Mountain View, CA, UISA), which allowed
close approximation between the ultra-
sound transducer and the prosthetic valve
(panel A). A 2 mm mobile vegetation was
visualised attached to one of the leaflets of
the aortic bioprosthetic valve (panel B;
video). Aortic valve replacement was per-
formed and fungal vegetation was con-
firmed by mycopathology. There was no
evidence of abscess formation. Eleven days
examined the role of ICE in the evaluation
79-year-old woman was transferred
to our hospital after a syncopal
episode that resulted in a cervical
after the operation, a pacemaker was
implanted for recurrent sinus arrest(aetiol-
ogy of syncope). The patient was dis-
These images illustrate a new use of ICE
endocarditis. Although a few studies have
of valvular pathology, its clinical role has
primarily been within the electrophysiology
laboratory to guide catheter placement. As
this technology continues to evolve, ICE
may supplement other imaging modalities
and find new clinical applications.
D Q Kolodner, D Shimbo, A R Magnano
To view video footage visit the
Fluoroscopy image demonstrating proximity of
the ultrasound probe (UP) and aortic valve (AV).
Intracardiac echocardiography view of the aortic
valve (AV) and left ventricular outflow tract with
mobile vegetation (Veg) on the aortic leaflet.
1120Buckley, Murphy, Byrne, et al