Implementing decision aids for cardiovascular disease prevention: stakeholder interviews and case studies in Australian primary care.

BACKGROUND: Australian cardiovascular disease (CVD) prevention guidelines recommend absolute CVD risk assessment, but less than half of eligible patients have the required risk factors recorded due to fragmented implementation over the last decade. Co-designed decision aids for general practitioners (GPs) and consumers have been developed that improve knowledge barriers to guideline-recommended CVD risk assessment and management. This study used a stakeholder consultation process to identify and pilot test the feasibility of implementation strategies for these decision aids in Australian primary care. METHODS: This mixed methods study included: (1) stakeholder consultation to map existing implementation strategies (2018-20); (2) interviews with 29 Primary Health Network (PHN) staff from all Australian states and territories to identify new implementation opportunities (2021); (3) pilot testing the feasibility of low, medium, and high resource implementation strategies (2019-21). Framework Analysis was used for qualitative data and Google analytics provided decision support usage data over time. RESULTS: Informal stakeholder discussions indicated a need to partner with existing programs delivered by the Heart Foundation and PHNs. PHN interviews identified the importance of linking decision aids with GP education resources, quality improvement activities, and consumer-focused prevention programs. Participants highlighted the importance of integration with general practice processes, such as business models, workflows, medical records and clinical audit software. Specific implementation strategies were identified as feasible to pilot during COVID-19: (1) low resource: adding website links to local health area guidelines for clinicians and a Heart Foundation toolkit for primary care providers; (2) medium resource: presenting at GP education conferences and integrating the resources into audit and feedback reports; (3) high resource: auto-populate the risk assessment and decision aids from patient records via clinical audit software. CONCLUSIONS: This research identified a wide range of feasible strategies to implement decision aids for CVD risk assessment and management. The findings will inform the translation of new CVD guidelines in primary care. Future research will use economic evaluation to explore the added value of higher versus lower resource implementation strategies.

Excess healthcare costs of psychological distress in young women: Evidence from linked national Medicare claims data.

The prevalence of mental health disorders in young adults is increasing, yet there is limited empirical evidence on its economic consequences. We contribute to the literature by estimating the healthcare costs of psychological distress using panel data of young women (aged 18-23 years with a 5-year follow-up) from the Australian Longitudinal Study on Women's Health and linked administrative data from Medicare Australia. Our empirical strategy is based on the classical two-part model of healthcare costs with individual specific fixed-effects. We complement our analysis with a test for selection on unobservables to address potential concerns of endogeneity. We find that young women with psychological distress have 15% higher annual healthcare costs (excluding hospital costs) than women with no psychological distress. A large proportion of these costs is driven by the use of antidepressants and the services of psychiatrists and psychologists. We further find that women with psychological distress have higher out-of-pocket costs on these mental health related services compared to non-mental health specific services. Additionally, we show that the effect of psychological distress on healthcare costs is highest during the first 6 months of onset, which gradually decreases afterwards. The findings justify the importance of policy initiatives towards early prevention and treatment of psychological distress, especially among young women.

Decision Support Tools for Coronary Artery Calcium Scoring in the Primary Prevention of Cardiovascular Disease Do Not Meet Health Literacy Needs: A Systematic Environmental Scan and Evaluation.

A shared decision-making approach is considered optimal in primary cardiovascular disease (CVD) prevention. Evidence-based patient decision aids can facilitate this but do not always meet patients' health literacy needs. Coronary artery calcium (CAC) scans are increasingly used in addition to traditional cardiovascular risk scores, but the availability of high-quality decision aids to support shared decision-making is unknown. We used an environmental scan methodology to review decision support for CAC scans and assess their suitability for patients with varying health literacy. We systematically searched for freely available web-based decision support tools that included information about CAC scans for primary CVD prevention and were aimed at the public. Eligible materials were independently evaluated using validated tools to assess qualification as a decision aid, understandability, actionability, and readability. We identified 13 eligible materials. Of those, only one qualified as a decision aid, and one item presented quantitative information about the potential harms of CAC scans. None presented quantitative information about both benefits and harms of CAC scans. Mean understandability was 68%, and actionability was 48%. Mean readability (12.8) was much higher than the recommended grade 8 level. Terms used for CAC scans were highly variable. Current materials available to people considering a CAC scan do not meet the criteria to enable informed decision-making, nor do they meet the health literacy needs of the general population. Clinical guidelines, including CAC scans for primary prevention, must be supported by best practice decision aids to support decision-making.

Kidney trajectory charts to assist general practitioners in the assessment of patients with reduced kidney function: a randomised vignette study.

OBJECTIVE: To investigate the decisional impact of an age-based chart of kidney function decline to support general practitioners (GPs) to appropriately interpret estimated glomerular filtration rate (eGFR) and identify patients with a clinically relevant kidney problem. DESIGN AND SETTING: Randomised vignette study PARTICIPANTS: 372 Australian GPs from August 2018 to November 2018. INTERVENTION: GPs were given two patient case scenarios: (1) an older woman with reduced but stable renal function and (2) a younger Aboriginal man with declining kidney function still in the normal range. One group was given an age-based chart of kidney function to assist their assessment of the patient (initial chart group); the second group was asked to assess the patients without the chart, and then again using the chart (delayed chart group). MAIN OUTCOME MEASURES: GPs' assessment of the likelihood-on a Likert scale-that the patients had chronic kidney disease (CKD) according to the usual definition or a clinical problem with their kidneys. RESULTS: Prior to viewing the age-based chart GPs were evenly distributed as to whether they thought case 1-the older woman-had CKD or a clinically relevant kidney problem. GPs who had initial access to the chart were less likely to think that the older woman had CKD, and less likely to think she had a clinically relevant problem with her kidneys than GPs who had not viewed the chart. After subsequently viewing the chart, 14% of GPs in the delayed chart group changed their opinion, to indicate she was unlikely to have a clinically relevant problem with her kidneys.Prior to viewing the chart, the majority of GPs (66%) thought case 2-the younger man-did not have CKD, and were evenly distributed as to whether they thought he had a clinically relevant kidney problem. In contrast, GPs who had initial access to the chart were more likely to think he had CKD and the majority (72%) thought he had a clinically relevant kidney problem. After subsequently viewing the chart, 37% of GPs in the delayed chart group changed their opinion to indicate he likely had a clinically relevant problem with his kidneys. CONCLUSIONS: Use of the chart changed GPs interpretation of eGFR, with increased recognition of the younger male patient's clinically relevant kidney problem, and increased numbers classifying the older female patient's kidney function as normal for her age. This study has shown the potential of an age-based kidney function chart to reduce both overdiagnosis and underdiagnosis.

Rates, costs and determinants of lumbar spine imaging in population-based women born in 1973-1978: Data from the Australian Longitudinal Study on Women's Health.

OBJECTIVE: There are concerns that lumbar spine imaging represents low value care. Our aim was to examine the use of lumbar spine imaging [radiography, computed tomography (CT), magnetic resonance imaging (MRI)] over 20 years, and costs and person-level characteristics of imaging in a large cohort of Australian women. METHODS: The Australian Longitudinal Study on Women's Health (ALSWH) is a longitudinal population-based survey of women randomly selected from national health insurance scheme (Medicare) database. This study examined 13458 women born in 1973-1978 who consented to link their ALSWH and Medical Benefits Scheme records. Self-reported data on demographics, body mass index, depression, physical and mental health, and back pain were collected in each survey performed in 1996, 2000, 2003, 2006, 2009, 2012, and 2015. Data on lumbar spine imaging from 1996 to 2015 were obtained from the Medical Benefits Scheme database. RESULTS: 38.9% of women underwent some form of lumbar spine imaging over 20 years. While radiography increased from 1996 to 2011 and decreased thereafter, CT and MRI continued to increase from 1996 to 2015. In women with self-reported back pain, depression and poorer physical health were associated with imaging, with no significant differences in types of imaging. Based on imaging rates in ALSWH, the estimated costs for Australian women aged 30-39 years were AU$51,735,649 over 2011-2015. CONCLUSIONS: Lumbar spine imaging was common in population-based Australian women, with rates increasing over 20 years. Depression and poor physical health were associated with lumbar spine imaging. Raising awareness of this in clinicians is likely to result in significant cost savings if clinical guidelines are followed, with the potential of freeing resources for high value care and health outcomes.

Implementing cardiovascular disease prevention guidelines to translate evidence-based medicine and shared decision making into general practice: theory-based intervention development, qualitative piloting and quantitative feasibility.

BACKGROUND: The use of cardiovascular disease (CVD) prevention guidelines based on absolute risk assessment is poor around the world, including Australia. Behavioural barriers amongst GPs and patients include capability (e.g. difficulty communicating/understanding risk) and motivation (e.g. attitudes towards guidelines/medication). This paper outlines the theory-based development of a website for GP guidelines, and piloting of a new risk calculator/decision aid. METHODS: Stage 1 involved identifying evidence-based solutions using the Behaviour Change Wheel (BCW) framework, informed by previous research involving 400 GPs and 600 patients/consumers. Stage 2 co-developed website content with GPs. Stage 3 piloted a prototype website at a national GP conference. Stage 4 iteratively improved the website based on "think aloud" interviews with GPs and patients. Stage 5 was a feasibility study to evaluate potential efficacy (guidelines-based recommendations for each risk category), acceptability (intended use) and demand (actual use over 1 month) amongst GPs (n = 98). RESULTS: Stage 1 identified GPs as the target for behaviour change; the need for a new risk calculator/decision aid linked to existing audit and feedback training; and online guidelines as a delivery format. Stage 2-4 iteratively improved content and format based on qualitative feedback from GP and patient user testing over three rounds of website development. Stage 5 suggested potential efficacy with improved identification of hypothetical high risk patients (from 26 to 76%) and recommended medication (from 57 to 86%) after viewing the website (n = 42), but prescribing to low risk patients remained similar (from 19 to 22%; n = 37). Most GPs (89%) indicated they would use the website in the next month, and 72% reported using it again after one month (n = 98). Open feedback identified implementation barriers including a need for integration with medical software, low health literacy resources and pre-consultation assessment. CONCLUSIONS: Following a theory-based development process and user co-design, the resulting intervention was acceptable to GPs with high intentions for use, improved identification of patient risk categories and more guidelines-based prescribing intentions for high risk but not low risk patients. The effectiveness of linking the intervention to clinical practice more closely to address implementation barriers will be evaluated in future research.

Should heart age calculators be used alongside absolute cardiovascular disease risk assessment?

BACKGROUND: National estimates of 'heart age' by government health organisations in the US, UK and China show most people have an older heart age than current age. While most heart age calculators are promoted as a communication tool for lifestyle change, they may also be used to justify medication when clinical guidelines advocate their use alongside absolute risk assessment. However, only those at high absolute risk of a heart attack or stroke are likely to benefit from medication, and it is not always clear how heart age relates to absolute risk. This article aims to: 1) explain how heart age calculation methods relate to absolute risk guidelines; 2) summarise research investigating whether heart age improves risk communication; and 3) discuss implications for the use of medication and shared decision making in clinical practice. MAIN BODY: There is a large and growing number of heart age models and online calculators, but the clinical meaning of an older heart age result is highly variable. An older heart age result may indicate low, moderate or high absolute risk of a heart attack or stroke in the next 5-10 years, and the same individual may receive a younger or older heart age result depending on which calculator is used. Heart age may help doctors convey the need to change lifestyle, but it cannot help patients make an informed choice about medication to reduce CVD risk. CONCLUSION: Interactive heart age tools may be helpful as a communication tool to initiate lifestyle change to reduce risk factors. However, absolute risk should be used instead of heart age to enable informed decision making about medication, to avoid unnecessary treatment of low risk people. Evidence-based decision aids that improve patient understanding of absolute risk should be considered as alternatives to heart age calculators for lifestyle and medication decisions.

Public Opinions about Overdiagnosis: A National Community Survey.

BACKGROUND: Despite evidence about the "modern epidemic" of overdiagnosis, and expanding disease definitions that medicalize more people, data are lacking on public views about these issues. Our objective was to measure public perceptions about overdiagnosis and views about financial ties of panels setting disease definitions. METHODS: We conducted a 15 minute Computer Assisted Telephone Interview with a randomly selected community sample of 500 Australians in January 2014. We iteratively developed and piloted a questionnaire, with a convenience sample (n=20), then with participants recruited by a research company (n=20). Questions included whether respondents had been informed about overdiagnosis; opinions on informing people; and views about financial ties among panels writing disease definitions. FINDINGS: Our sample was generally representative, but included a higher proportion of females and seniors, typical of similar surveys. American Association for Public Opinion Research response rate was 20% and cooperation rate was 44%. Only 10% (95% CI 8%-13%) of people reported ever being told about overdiagnosis by a doctor. 18% (95% CI 11%-28%) of men who reported having prostate cancer screening, and 10% (95% CI 6%-15%) of women who reported having mammography said they were told about overdiagnosis. 93% (95% CI 90%-95%) agreed along with screening benefits, people should be informed about overdiagnosis. On panels setting disease definitions, 78% (95% CI 74%-82%) felt ties to pharmaceutical companies inappropriate, and 91% (95% CI 82%-100%) believed panels should have a minority or no members with ties. Limitations included questionnaire novelty and complexity. CONCLUSIONS: A small minority of Australians surveyed, including those reporting being screened for prostate or breast cancer, reported being informed of overdiagnosis; most believed people should be informed; and a majority felt it inappropriate that doctors with ties to pharmaceutical companies write disease definitions. Results suggest strategies to better inform people about overdiagnosis, and review disease definition processes, have significant public sympathy.

How do general practitioners and patients make decisions about cardiovascular disease risk?

OBJECTIVE: Although current guidelines around the world recommend using absolute risk (AR) thresholds to decide whether cardiovascular disease (CVD) risk should be managed with lifestyle or medication, the use of AR in clinical practice is limited. The aim of this study was to explore the factors that influence general practitioner (GP) and patient decision making about CVD risk management, including the role of risk perception. METHODS: Qualitative descriptive study involving semi-structured interviews with 25 GPs and 38 patients in Australia in 2011-2012. Transcribed audio-recordings were thematically coded and a Framework Analysis method was used. RESULTS: GPs rarely mentioned AR thresholds but were influenced by their subjective perception of the patient's risk and motivation, and their own attitudes toward prevention, including concerns about medication side effects and the efficacy of lifestyle change. Patients were influenced by individual risk factors, their own motivation to change lifestyle, and attitudes toward medication: initially negative, but this improved if medication was more effective than lifestyle. High perceived risk led to medication being recommended by GPs and accepted by patients, but this was not necessarily based on AR. Patient perceptions of high risk also increased motivation to change lifestyle, particularly if they were resistant to the idea of taking medication. CONCLUSIONS: Perceived risk, motivation, and attitudes appeared to be more important than AR thresholds in this study. CVD risk management guidelines could be more useful if they include strategies to help GPs consider patients' risk perception, motivation, and attitudes as well as evidence-based recommendations.

Deliberative democracy and cancer screening consent: a randomised control trial of the effect of a community jury on men's knowledge about and intentions to participate in PSA screening.

OBJECTIVE: Prostate-specific antigen (PSA) screening is controversial. A community jury allows presentation of complex information and may clarify how participants view screening after being well-informed. We examined whether participating in a community jury had an effect on men's knowledge about and their intention to participate in PSA screening. DESIGN: Random allocation to either a 2-day community jury or a control group, with preassessment, postassessment and 3-month follow-up assessment. SETTING: Participants from the Gold Coast (Australia) recruited via radio, newspaper and community meetings. PARTICIPANTS: Twenty-six men aged 50-70 years with no previous diagnosis of prostate cancer. INTERVENTION: The control group (n=14) received factsheets on PSA screening. Community jury participants (n=12) received the same factsheets and further information about screening for prostate cancer. In addition, three experts presented information on PSA screening: a neutral scientific advisor provided background information, one expert emphasised the potential benefits of screening and another expert emphasised the potential harms. Participants discussed information, asked questions to the experts and deliberated on personal and policy decisions. MAIN OUTCOME AND MEASURES: Our primary outcome was change in individual intention to have a PSA screening test. We also assessed knowledge about screening for prostate cancer. RESULTS: Analyses were conducted using intention-to-treat. Immediately after the jury, the community jury group had less intention-to-screen for prostate cancer than men in the control group (effect size=-0.6 SD, p=0.05). This was sustained at 3-month follow-up. Community jury men also correctly identified PSA test accuracy and considered themselves more informed (effect size=1.2 SD, p<0.001). CONCLUSIONS: Evidence-informed deliberation of the harms and benefits of PSA screening effects men's individual choice to be screened for prostate cancer. Community juries may be a valid method for eliciting target group input to policy decisions. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12612001079831).

A multifaceted quality improvement intervention for CVD risk management in Australian primary healthcare: a protocol for a process evaluation.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Despite the widespread availability of evidence-based clinical guidelines and validated risk predication equations for prevention and management of CVD, their translation into routine practice is limited. We developed a multifaceted quality improvement intervention for CVD risk management which incorporates electronic decision support, patient risk communication tools, computerised audit and feedback tools, and monthly, peer-ranked performance feedback via a web portal. The intervention was implemented in a cluster randomised controlled trial in 60 primary healthcare services in Australia. Overall, there were improvements in risk factor recording and in prescribing of recommended treatments among under-treated individuals, but it is unclear how this intervention was used in practice and what factors promoted or hindered its use. This information is necessary to optimise intervention impact and maximally implement it in a post-trial context. In this study protocol, we outline our methods to conduct a theory-based, process evaluation of the intervention. Our aims are to understand how, why, and for whom the intervention produced the observed outcomes and to develop effective strategies for translation and dissemination. METHODS/DESIGN: We will conduct four discrete but inter-related studies taking a mixed methods approach. Our quantitative studies will examine (1) the longer term effectiveness of the intervention post-trial, (2) patient and health service level correlates with trial outcomes, and (3) the health economic impact of implementing the intervention at scale. The qualitative studies will (1) identify healthcare provider perspectives on implementation barriers and enablers and (2) use video ethnography and patient semi-structured interviews to understand how cardiovascular risk is communicated in the doctor/patient interaction both with and without the use of intervention. We will also assess the costs of implementing the intervention in Australian primary healthcare settings which will inform scale-up considerations. DISCUSSION: This mixed methods evaluation will provide a detailed understanding of the process of implementing a quality improvement intervention and identify the factors that might influence scalability and sustainability. TRIALS REGISTRATION: 12611000478910.

General practitioners' use of absolute risk versus individual risk factors in cardiovascular disease prevention: an experimental study.

OBJECTIVE: To understand general practitioners' (GPs) use of individual risk factors (blood pressure and cholesterol levels) versus absolute risk in cardiovascular disease (CVD) risk management decision-making. DESIGN: Randomised experiment. Absolute risk, systolic blood pressure (SBP), cholesterol ratio (total cholesterol/high-density lipoprotein (TC/HDL)) and age were systematically varied in hypothetical cases. High absolute risk was defined as 5-year risk of a cardiovascular event >15%, high blood pressure levels varied between SBP 147 and 179 mm Hg and high cholesterol (TC/HDL ratio) between 6.5 and 7.2 mmol/L. SETTING: 4 GP conferences in Australia. PARTICIPANTS: 144 Australian GPs. OUTCOMES: GPs indicated whether they would prescribe cholesterol and/or blood pressure lowering medication. Analyses involved logistic regression. RESULTS: For patients with high blood pressure: 93% (95% CI 86% to 96%) of high absolute risk patients and 83% (95% CI 76% to 88%) of lower absolute risk patients were prescribed blood pressure medication. Conversely, 30% (95% CI 25% to 36%) of lower blood pressure patients were prescribed blood pressure medication if absolute risk was high and 4% (95% CI 3% to 5%) if lower. 69% of high cholesterol/high absolute risk patients were prescribed cholesterol medication (95% CI 61% to 77%) versus 34% of high cholesterol/lower absolute risk patients (95% CI 28% to 41%). 36% of patients with lower cholesterol (95% CI 30% to 43%) were prescribed cholesterol medication if absolute risk was high versus 10% if lower (95% CI 8% to 13%). CONCLUSIONS: GPs' decision-making was more consistent with the management of individual risk factors than an absolute risk approach, especially when prescribing blood pressure medication. The results suggest medical treatment of lower risk patients (5-year risk of CVD event <15%) with mildly elevated blood pressure or cholesterol levels is likely to occur even when an absolute risk assessment is specifically provided. The results indicate a need for improving uptake of absolute risk guidelines and GP understanding of the rationale for using absolute risk.

Development and validation of the Emergency Department Assessment of Chest pain Score and 2 h accelerated diagnostic protocol.

OBJECTIVE: Risk scores and accelerated diagnostic protocols can identify chest pain patients with low risk of major adverse cardiac event who could be discharged early from the ED, saving time and costs. We aimed to derive and validate a chest pain score and accelerated diagnostic protocol (ADP) that could safely increase the proportion of patients suitable for early discharge. METHODS: Logistic regression identified statistical predictors for major adverse cardiac events in a derivation cohort. Statistical coefficients were converted to whole numbers to create a score. Clinician feedback was used to improve the clinical plausibility and the usability of the final score (Emergency Department Assessment of Chest pain Score [EDACS]). EDACS was combined with electrocardiogram results and troponin results at 0 and 2 h to develop an ADP (EDACS-ADP). The score and EDACS-ADP were validated and tested for reproducibility in separate cohorts of patients. RESULTS: In the derivation (n = 1974) and validation (n = 608) cohorts, the EDACS-ADP classified 42.2% (sensitivity 99.0%, specificity 49.9%) and 51.3% (sensitivity 100.0%, specificity 59.0%) as low risk of major adverse cardiac events, respectively. The intra-class correlation coefficient for categorisation of patients as low risk was 0.87. CONCLUSION: The EDACS-ADP identified approximately half of the patients presenting to the ED with possible cardiac chest pain as having low risk of short-term major adverse cardiac events, with high sensitivity. This is a significant improvement on similar, previously reported protocols. The EDACS-ADP is reproducible and has the potential to make considerable cost reductions to health systems.

General practitioners' use of different cardiovascular risk assessment strategies: a qualitative study.

OBJECTIVES: To identify factors that influence the extent to which general practitioners use absolute risk (AR) assessment in cardiovascular disease (CVD) risk assessment. DESIGN, SETTING AND PARTICIPANTS: Semi-structured interviews with 25 currently practising GPs from eight Divisions of General Practice in New South Wales, Australia, between October 2011 and May 2012. Data were analysed using framework analysis. RESULTS: The study identified five strategies that GPs use with patients in different situations, defined in terms of the extent to which AR was used and the reasons given for this: the AR-focused strategy, used when AR assessment was considered useful for the patient; the AR-adjusted strategy, used to account for additional risk factors such as family history; the clinical judgement strategy, used when GPs considered that their judgement took multiple risk factors into account as effectively as AR; the passive disregard strategy, used when GPs lacked sufficient time, access or experience to use AR; and the active disregard strategy, used when AR was considered to be inappropriate for the patient. The strategies were linked with different opportunity, capability and motivation barriers to the use of AR. CONCLUSIONS: This study provides an in-depth insight into the factors that influence GPs' use of AR in CVD risk assessment. The results suggest that GPs use a range of strategies in different situations, so different approaches may be required to improve the use of AR guidelines in practice.

Information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing: a systematic review.

BACKGROUND: Pharmaceutical companies spent $57.5 billion on pharmaceutical promotion in the United States in 2004. The industry claims that promotion provides scientific and educational information to physicians. While some evidence indicates that promotion may adversely influence prescribing, physicians hold a wide range of views about pharmaceutical promotion. The objective of this review is to examine the relationship between exposure to information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing. METHODS AND FINDINGS: We searched for studies of physicians with prescribing rights who were exposed to information from pharmaceutical companies (promotional or otherwise). Exposures included pharmaceutical sales representative visits, journal advertisements, attendance at pharmaceutical sponsored meetings, mailed information, prescribing software, and participation in sponsored clinical trials. The outcomes measured were quality, quantity, and cost of physicians' prescribing. We searched Medline (1966 to February 2008), International Pharmaceutical Abstracts (1970 to February 2008), Embase (1997 to February 2008), Current Contents (2001 to 2008), and Central (The Cochrane Library Issue 3, 2007) using the search terms developed with an expert librarian. Additionally, we reviewed reference lists and contacted experts and pharmaceutical companies for information. Randomized and observational studies evaluating information from pharmaceutical companies and measures of physicians' prescribing were independently appraised for methodological quality by two authors. Studies were excluded where insufficient study information precluded appraisal. The full text of 255 articles was retrieved from electronic databases (7,185 studies) and other sources (138 studies). Articles were then excluded because they did not fulfil inclusion criteria (179) or quality appraisal criteria (18), leaving 58 included studies with 87 distinct analyses. Data were extracted independently by two authors and a narrative synthesis performed following the MOOSE guidelines. Of the set of studies examining prescribing quality outcomes, five found associations between exposure to pharmaceutical company information and lower quality prescribing, four did not detect an association, and one found associations with lower and higher quality prescribing. 38 included studies found associations between exposure and higher frequency of prescribing and 13 did not detect an association. Five included studies found evidence for association with higher costs, four found no association, and one found an association with lower costs. The narrative synthesis finding of variable results was supported by a meta-analysis of studies of prescribing frequency that found significant heterogeneity. The observational nature of most included studies is the main limitation of this review. CONCLUSIONS: With rare exceptions, studies of exposure to information provided directly by pharmaceutical companies have found associations with higher prescribing frequency, higher costs, or lower prescribing quality or have not found significant associations. We did not find evidence of net improvements in prescribing, but the available literature does not exclude the possibility that prescribing may sometimes be improved. Still, we recommend that practitioners follow the precautionary principle and thus avoid exposure to information from pharmaceutical companies. Please see later in the article for the Editors' Summary.

Qualification versus validation of biomarkers.

The phases of research used to evaluate new drugs provide a useful reference point for determining the studies that need to be conducted to evaluate new biomarkers. However, biomarkers do not have a single pathway for changing health outcomes and may be used for a variety of purposes, such as improving diagnostic criteria, improving prognosis, improving the monitoring of disease or as a measurement of health outcomes. The impact on health outcomes is also less direct and is dependent on the sequence of actions taken as a consequence of the test results. The different purposes of biomarkers and the less direct effect on health outcomes require different study designs to those used for the evaluation of pharmaceutical products and a more careful interpretation of results. Greater collaboration between researchers designing laboratory-based qualification studies and researchers designing clinical validation studies could achieve a process of evaluation for biomarkers that is both reliable and efficient.