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1.  Patient accounts of diagnostic testing for familial hypercholesterolaemia: comparing responses to genetic and non-genetic testing methods 
BMC Medical Genetics  2012;13:87.
Background
Continuing developments in genetic testing technology together with research revealing gene-disease associations have brought closer the potential for genetic screening of populations. A major concern, as with any screening programme, is the response of the patient to the findings of screening, whether the outcome is positive or negative. Such concern is heightened for genetic testing, which it is feared may elicit stronger reactions than non-genetic testing.
Methods
This paper draws on thematic analysis of 113 semi-structured interviews with 39 patients being tested for familial hypercholesterolaemia (FH), an inherited predisposition to early-onset heart disease. It examines the impact of disease risk assessments based on both genetic and non-genetic information, or solely non-genetic information.
Results
The impact of diagnostic testing did not seem to vary according to whether or not genetic information was used. More generally, being given a positive or negative diagnosis of FH had minimal discernible impact on people's lives as they maintained the continuity of their beliefs and behaviour.
Conclusions
The results suggest that concerns about the use of genetic testing in this context are unfounded, a conclusion that echoes findings from studies in this and other health contexts.
doi:10.1186/1471-2350-13-87
PMCID: PMC3495051  PMID: 22994377
Behaviour change; Genetics; Genetic testing; Health behaviour; Risk; Qualitative
2.  Trial Protocol: Communicating DNA-based risk assessments for Crohn's disease: a randomised controlled trial assessing impact upon stopping smoking 
BMC Public Health  2011;11:44.
Background
Estimates of the risk of developing Crohn's disease (CD) can be made using DNA testing for mutations in the NOD2 (CARD15) gene, family history, and smoking status. Smoking doubles the risk of CD, a risk that is reduced by stopping. CD therefore serves as a timely and novel paradigm within which to assess the utility of predictive genetic testing to motivate behaviour change to reduce the risk of disease. The aim of the study is to describe the impact upon stopping smoking of communicating a risk of developing CD that incorporates DNA analysis. We will test the following main hypothesis:
Smokers who are first degree relatives (FDRs) of CD probands are more likely to make smoking cessation attempts following communication of risk estimates of developing CD that incorporate DNA analysis, compared with an equivalent communication that does not incorporate DNA analysis.
Methods/design
A parallel groups randomised controlled trial in which smokers who are FDRs of probands with CD are randomly allocated in families to undergo one of two types of assessment of risk for developing CD based on either:
i. DNA analysis, family history of CD and smoking status, or
ii. Family history of CD and smoking status
The primary outcome is stopping smoking for 24 hours or longer in the six months following provision of risk information. The secondary outcomes are seven-day smoking abstinence at one week and six month follow-ups. Randomisation of 470 smoking FDRs of CD probands, with 400 followed up (85%), provides 80% power to detect a difference in the primary outcome of 14% between randomised arms, at the 5% significance level.
Discussion
This trial provides one of the strongest tests to date of the impact of communicating DNA-based risk assessment on risk-reducing behaviour change. Specific issues regarding the choice of trial design are discussed.
Trial Registration
ISRCTN: ISRCTN21633644
doi:10.1186/1471-2458-11-44
PMCID: PMC3036624  PMID: 21247480
3.  Trial Protocol: Using genotype to tailor prescribing of nicotine replacement therapy: a randomised controlled trial assessing impact of communication upon adherence 
BMC Public Health  2010;10:680.
Background
The behavioural impact of pharmacogenomics is untested; informing smokers of genetic test results for responsiveness to smoking cessation medication may increase adherence to this medication. The objective of this trial is to estimate the impact upon adherence to nicotine replacement therapy (NRT) of informing smokers that their oral dose of NRT has been tailored to a DNA analysis. Hypotheses to be tested are as follows:
I Adherence to NRT is greater among smokers informed that their oral dose of NRT is tailored to an analysis of DNA (genotype), compared to one tailored to nicotine dependence questionnaire score (phenotype).
II Amongst smokers who fail to quit at six months, motivation to make another quit attempt is lower when informed that their oral dose of NRT was tailored to genotype rather than phenotype.
Methods/Design
An open label, parallel groups randomised trial in which 630 adult smokers (smoking 10 or more cigarettes daily) using National Health Service (NHS) stop smoking services in primary care are randomly allocated to one of two groups:
i. NRT oral dose tailored by DNA analysis (OPRM1 gene) (genotype), or
ii. NRT oral dose tailored by nicotine dependence questionnaire score (phenotype)
The primary outcome is proportion of prescribed NRT consumed in the first 28 days following an initial quit attempt, with the secondary outcome being motivation to make another quit attempt, amongst smokers not abstinent at six months. Other outcomes include adherence to NRT in the first seven days and biochemically validated smoking abstinence at six months. The primary outcome will be collected on 630 smokers allowing sufficient power to detect a 7.5% difference in mean proportion of NRT consumed using a two-tailed test at the 5% level of significance between groups. The proportion of all NRT consumed in the first four weeks of quitting will be compared between arms using an independent samples t-test and by estimating the 95% confidence interval for observed between-arm difference in mean NRT consumption (Hypothesis I). Motivation to make another quit attempt will be compared between arms in those failing to quit by six months (Hypothesis II).
Discussion
This is the first clinical trial evaluating the behavioural impact on adherence of prescribing medication using genetic rather than phenotypic information. Specific issues regarding the choice of design for trials of interventions of this kind are discussed.
Trial details
Funder: Medical Research Council (MRC)
Grant number: G0500274
ISRCTN: 14352545
Date trial stated: June 2007
Expected end date: December 2009
Expected reporting date: December 2010
doi:10.1186/1471-2458-10-680
PMCID: PMC2996370  PMID: 21062464
4.  General practitioners' perceptions of the effectiveness of medical interventions: an exploration of underlying constructs 
Background
Many interventions shown to be effective through clinical trials are not readily implemented in clinical practice. Unfortunately, little is known regarding how clinicians construct their perceptions of the effectiveness of medical interventions. This study aims to explore general practitioners' perceptions of the nature of 'effectiveness'.
Methods
The design was qualitative in nature using the repertory grid technique to elicit the constructs underlying the perceived effectiveness of a range of medical interventions. Eight medical interventions were used as stimuli (diclophenac to reduce acute pain, cognitive behaviour therapy to treat depression, weight loss surgery to achieve weight loss, diet and exercise to prevent type 2 diabetes, statins to prevent heart disease, stopping smoking to prevent heart disease, nicotine replacement therapy to stop smoking, and stop smoking groups to stop smoking). The setting involved face-to-face interviews followed by questionnaires in London Primary Care Trusts. Participants included a random sample of 13 general practitioners.
Results
Analysis of the ratings showed that the constructs clustered around two dimensions: low patient effort versus high patient effort (dimension one), and small impact versus large impact (dimension two). Dimension one represented constructs such as 'success requires little motivation', 'not a lifestyle intervention', and 'health-care professional led intervention'. Dimension two represented constructs such as 'weak and/or minimal evidence of effectiveness', 'small treatment effect for users', 'a small proportion of users will benefit' and 'not cost-effective'. Constructs within each dimension were closely related.
Conclusions
General practitioners judged the effectiveness of medical interventions by considering two broad dimensions: the extent to which interventions involve patient effort, and the size of their impact. The latter is informed by trial evidence, but the patient effort required to achieve effectiveness seems to be based on clinical judgement. Some of the failure of evidence-based medicine to be implemented may be more explicable if both dimensions were attended to.
doi:10.1186/1748-5908-5-17
PMCID: PMC2827366  PMID: 20158896
5.  Effect of communicating DNA based risk assessments for Crohn’s disease on smoking cessation: randomised controlled trial 
Objective To test the hypothesis that communicating risk of developing Crohn’s disease based on genotype and that stopping smoking can reduce this risk, motivates behaviour change among smokers at familial risk.
Design Parallel group, cluster randomised controlled trial.
Setting Families with Crohn’s disease in the United Kingdom.
Participants 497 smokers (mean age 42.6 (SD 14.4) years) who were first degree relatives of probands with Crohn’s disease, with outcomes assessed on 209/251 (based on DNA analysis) and 217/246 (standard risk assessment).
Intervention Communication of risk assessment for Crohn’s disease by postal booklet based on family history of the disease and smoking status alone, or with additional DNA analysis for the NOD2 genotype. Participants were then telephoned by a National Health Service Stop Smoking counsellor to review the booklet and deliver brief standard smoking cessation intervention. Calls were tape recorded and a random subsample selected to assess fidelity to the clinical protocol.
Main outcome measure The primary outcome was smoking cessation for 24 hours or longer, assessed at six months.
Results The proportion of participants stopping smoking for 24 hours or longer did not differ between arms: 35% (73/209) in the DNA arm versus 36% (78/217) in the non-DNA arm (difference −1%, 95% confidence interval −10% to 8%, P=0.83). The proportion making a quit attempt within the DNA arm did not differ between those who were told they had mutations putting them at increased risk (36%), those told they had none (35%), and those in the non-DNA arm (36%).
Conclusion Among relatives of patients with Crohn’s disease, feedback of DNA based risk assessments does not motivate behaviour change to reduce risk any more or less than standard risk assessment. These findings accord with those across a range of populations and behaviours. They do not support the promulgation of commercial DNA based tests nor the search for gene variants that confer increased risk of common complex diseases on the basis that they effectively motivate health related behaviour change.
Trial registration Current Controlled Trials ISRCTN21633644.
doi:10.1136/bmj.e4708
PMCID: PMC3401124  PMID: 22822007

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