Jon Emery

Designing and evaluating complex interventions to improve health care

Determining the effectiveness of complex interventions can be difficult and time consuming. Neil C Campbell and colleagues explain the importance of ground work in getting usable results

CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis.

Purpose: Two common variant alleles of the cytochrome CYP2C9 (CYP2C9*2 and CYP2C9*3) lead to reduced warfarin metabolism in vitro and in vivo. The study objective was to examine the strength and quality of existing evidence about CYP2C9 gene variants and clinical outcomes in warfarin-treated patients.Methods: The study was a systematic review and meta-analysis. Multiple electronic databases were searched, references identified from bibliographies were sought, and experts and authors of primary studies were also contacted. Strict review inclusion criteria were determined. Three reviewers independently extracted data using prepiloted proformas.Results: In all, 11 studies meeting review inclusion criteria were identified (3029 patients). Nine were included in the meta-analyses (2775 patients). Random effects meta-analyses were performed; statistical heterogeneity and inconsistency was assessed. Twenty percent of patients studied carry a variant allele: CYP2C9*2 12.2% (9.7%–15.0%) and CYP2C9*3, 7.9% (6.5%–9.7%). Mean difference in daily warfarin dose: for CYP2C9*2, the reduction was 0.85 mg (0.60–1.11 mg), a 17% reduction. For CYP2C9*3, the reduction was 1.92 mg (1.37–2.47 mg), a 37% reduction. For CYP2C9*2 or *3, the reduction was 1.47 mg (1.24–1.71 mg), a 27% reduction. The relative bleeding risk for CYP2C9*2 was 1.91 (1.16–3.17) and for CYP2C9*3 1.77 (1.07–2.91). For either variant, the relative risk was 2.26 (1.36–3.75).Conclusions: Patients with CYP2C9*2 and CYP2C9*3 alleles have lower mean daily warfarin doses and a greater risk of bleeding. Testing for gene variants could potentially alter clinical management in patients commencing warfarin. Evidence for the clinical utility and cost-effectiveness of genotyping is needed before routine testing can be recommended.

Lay Understanding of Familial Risk of Common Chronic Diseases: A Systematic Review and Synthesis of Qualitative Research

PURPOSE Although the family history is increasingly used for genetic risk assessment of common chronic diseases in primary care, evidence suggests that lay understanding about inheritance may conflict with medical models. This study systematically reviewed and synthesized the qualitative literature exploring understanding about familial risk held by persons with a family history of cancer, coronary artery disease, and diabetes mellitus. METHODS Twenty-two qualitative articles were found after a comprehensive literature search and were critically appraised; 11 were included. A meta-ethnographic approach was used to translate the studies across each other, synthesize the translation, and express the synthesis. RESULTS A dynamic process emerged by which a personal sense of vulnerability included some features that mirror the medical factors used to assess risk, such as the number of affected relatives. Other features are more personal, such as experience of a relative’s disease, sudden or premature death, perceived patterns of illness relating to gender or age at death, and comparisons between a person and an affected relative. The developing vulnerability is interpreted using personal mental models, including models of disease causation, inheritance, and fatalism. A person’s sense of vulnerability affects how that person copes with, and attempts to control, any perceived familial risk. CONCLUSIONS Persons with a family history of a common chronic disease develop a personal sense of vulnerability that is informed by the salience of their family history and interpreted within their personal models of disease causation and inheritance. Features that give meaning to familial risk may be perceived differently by patients and professionals. This review identifies key areas for health professionals to explore with patients that may improve the effectiveness of communication about disease risk and management.

The Aarhus statement: improving design and reporting of studies on early cancer diagnosis

Early diagnosis is a key factor in improving the outcomes of cancer patients. A greater understanding of the pre-diagnostic patient pathways is vital yet, at present, research in this field lacks consistent definitions and methods. As a consequence much early diagnosis research is difficult to interpret. A consensus group was formed with the aim of producing guidance and a checklist for early cancer-diagnosis researchers. A consensus conference approach combined with nominal group techniques was used. The work was supported by a systematic review of early diagnosis literature, focussing on existing instruments used to measure time points and intervals in early cancer-diagnosis research. A series of recommendations for definitions and methodological approaches is presented. This is complemented by a checklist that early diagnosis researchers can use when designing and conducting studies in this field. The Aarhus checklist is a resource for early cancer-diagnosis research that should promote greater precision and transparency in both definitions and methods. Further work will examine whether the checklist can be readily adopted by researchers, and feedback on the guidance will be used in future updates.

Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study

Objectives To determine the accuracy and acceptability to patients of non-endoscopic screening for Barrett’s oesophagus, using an ingestible oesophageal sampling device (Cytosponge) coupled with immunocytochemisty for trefoil factor 3. Design Prospective cohort study. Setting 12 UK general practices, with gastroscopies carried out in one hospital endoscopy unit. Participants 504 of 2696 eligible patients (18.7%) aged 50 to 70 years with a previous prescription for an acid suppressant (H2 receptor antagonist or proton pump inhibitor) for more than three months in the past five years. Main outcome measures Sensitivity and specificity estimates for detecting Barrett’s oesophagus compared with gastroscopy as the ideal method, and patient anxiety (short form Spielberger state trait anxiety inventory, impact of events scale) and acceptability (visual analogue scale) of the test. Results 501 of 504 (99%) participants (median age 62, male to female ratio 1:1.2) successfully swallowed the Cytosponge. No serious adverse events occurred. In total, 3.0% (15/501) had an endoscopic diagnosis of Barrett’s oesophagus (≥1 cm circumferential length, median circumferential and maximal length of 2 cm and 5 cm, respectively) with intestinal metaplasia. Compared with gastroscopy the sensitivity and specificity of the test was 73.3% (95% confidence interval 44.9% to 92.2%) and 93.8% (91.3% to 95.8%) for 1 cm or more circumferential length and 90.0% (55.5% to 99.7%) and 93.5% (90.9% to 95.5%) for clinically relevant segments of 2 cm or more. Most participants (355/496, 82%, 95% confidence interval 78.9% to 85.1%) reported low levels of anxiety before the test, and scores remained within normal limits at follow-up. Less than 4.5% (2.8% to 6.1%) of participants reported psychological distress a week after the procedure. Conclusions The performance of the Cytosponge test was promising and the procedure was well tolerated. These data bring screening for Barrett’s oesophagus into the realm of possibility. Further evaluation is recommended.

The Andersen Model of Total Patient Delay: A Systematic Review of Its Application in Cancer Diagnosis:

Objective Patient pathways to presentation to health care professionals and initial management in primary care are key determinants of outcomes in cancer. Reducing diagnostic delays may result in improved prognosis and increase the proportion of early stage cancers identified. Investigating diagnostic delay could be facilitated by use of a robust theoretical framework. We systematically reviewed the literature reporting the application of Andersens Model of Total Patient Delay (delay stages: appraisal, illness, behavioural, scheduling, treatment) in studies which assess cancer diagnosis. Methods We searched four electronic databases and conducted a narrative synthesis. Inclusion criteria were studies which: reported primary research, focused on cancer diagnosis and explicitly applied one or more stages of the Andersen Model in the collection or analysis of data. Results The vast majority of studies of diagnostic delay in cancer have not applied a theoretical model to inform data collection or reporting. Ten papers (reporting eight studies) met our inclusion criteria: three studied several cancers. The studies were heterogeneous in their methods and quality. The review confirmed that there are clearly identifiable stages between the recognition of a symptom, first presentation to a health care professional, subsequent diagnosis and initiation of treatment. There was strong evidence to support the existence and importance of appraisal and treatment delay as defined in the Andersen Model, although treatment delay requires expansion. There was some evidence to support scheduling delay which may be contributed to by both patient and the health service. Illness delay was often difficult to distinguish from appraisal delay. It was less clear whether behavioural delay exists as a separate significant stage. Conclusions Greater consistency is required in the conduct and reporting of studies of diagnostic delay in cancer. We propose refinements to the Andersen Model which could be used to increase its validity and improve the consistency of reporting in future studies.

The challenge of integrating genetic medicine into primary care

The likely increases in availability of DNA based tests and demand by patients for genetic information and advice mean that primary care practitioners will need to become genetically literate. 1 2 Genetic medicine is already beginning to enter the realms of primary care through the availability of testing for predisposition to certain cancers and carrier screening and diagnostic tests for common recessive disorders such as cystic fibrosis and hereditary haemochromatosis. For the near future these issues will probably remain the focus of genetic medicine in primary care, but this could shift if pharmacogenetic research fulfils even some of its early promises. We discuss the implications of genetic advances for primary care, how genetic medicine could be integrated into primary care, and the skills that primary care practitioners will need to provide advice. #### Summary points Primary care practitioners need to become genetically literate Currently the most important elements for primary care are prediction of risk of certain cancers and carrier screening for common autosomal recessive conditions such as cystic fibrosis Pharmacogenetics will become increasingly relevant in decisions around prescribing Integrating elements of genetic medicine into primary care will require the development of generic skills in genetic risk assessment and communication A multifaceted approach, including community genetic counsellors, primary care genetic specialists, educational programmes, and computerised decision support, is required to support the acquisition of genetic skills in primary care We searched Medline and Embase for relevant papers, combining terms relating to primary care and clinical genetics. We included papers identified from a previous systematic review of primary research on the role of family practice in genetics3 and relevant papers published subsequently. The papers were heterogeneous in their focus and methods, and, when appropriate, we state the evidence on which our statements are based. As more is learned about the genetic aspects of …

Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes? Systematic review

Background:It is unclear whether more timely cancer diagnosis brings favourable outcomes, with much of the previous evidence, in some cancers, being equivocal. We set out to determine whether there is an association between time to diagnosis, treatment and clinical outcomes, across all cancers for symptomatic presentations.Methods:Systematic review of the literature and narrative synthesis.Results:We included 177 articles reporting 209 studies. These studies varied in study design, the time intervals assessed and the outcomes reported. Study quality was variable, with a small number of higher-quality studies. Heterogeneity precluded definitive findings. The cancers with more reports of an association between shorter times to diagnosis and more favourable outcomes were breast, colorectal, head and neck, testicular and melanoma.Conclusions:This is the first review encompassing many cancer types, and we have demonstrated those cancers in which more evidence of an association between shorter times to diagnosis and more favourable outcomes exists, and where it is lacking. We believe that it is reasonable to assume that efforts to expedite the diagnosis of symptomatic cancer are likely to have benefits for patients in terms of improved survival, earlier-stage diagnosis and improved quality of life, although these benefits vary between cancers.

Familial hypercholesterolaemia: A model of care for Australasia

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated. To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described. This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification.

The expanding role of primary care in cancer control

The nature of cancer control is changing, with an increasing emphasis, fuelled by public and political demand, on prevention, early diagnosis, and patient experience during and after treatment. At the same time, primary care is increasingly promoted, by governments and health funders worldwide, as the preferred setting for most health care for reasons of increasing need, to stabilise health-care costs, and to accommodate patient preference for care close to home. It is timely, then, to consider how this expanding role for primary care can work for cancer control, which has long been dominated by highly technical interventions centred on treatment, and in which the contribution of primary care has been largely perceived as marginal. In this Commission, expert opinion from primary care and public health professionals with academic and clinical cancer expertise—from epidemiologists, psychologists, policy makers, and cancer specialists—has contributed to a detailed consideration of the evidence for cancer control provided in primary care and community care settings. Ranging from primary prevention to end-of-life care, the scope for new models of care is explored, and the actions needed to effect change are outlined. The strengths of primary care—its continuous, coordinated, and comprehensive care for individuals and families—are particularly evident in prevention and diagnosis, in shared follow-up and survivorship care, and in end-of-life care. A strong theme of integration of care runs throughout, and its elements (clinical, vertical, and functional) and the tools needed for integrated working are described in detail. All of this change, as it evolves, will need to be underpinned by new research and by continuing and shared multiprofessional development.