Testing Of Treatment Strategies Research Articles

Accounting for Capacity Constraints In Economic Evaluations of Stratified Medicine: A Systematic Review

Stratified medicines are viewed as promising interventions to safely, effectively and cost-effectively target treatment to eligible sub-groups of patients. However, the adoption of stratified medicines into practice has been slower than anticipated. Regulatory approval and reimbursement of stratified medicines creates an immediate demand for companion-diagnostic tests which were either not previously available or not prognostically useful. Health system capacity constraints can slow the implementation of stratified medicines and potentially influence their relative cost-effectiveness. This study aimed to identify if, and how, previous economic evaluations of stratified medicines had accounted for capacity constraints and the potential impact on relative cost-effectiveness. A meta-review conducted in February 2017 used an electronic search of the EMBASE and MEDLINE databases to identify all previous systematic reviews of economic evaluations relevant to stratified medicines. Primary economic evaluations of interventions of a test-treat strategy were then collated from the published reviews. All extracted data were tabulated and a narrative analysis was used to identify whether studies had discussed potential capacity issues and whether they had used formal methods to account for these in the analysis. This study yielded 47 systematic reviews of economic evaluations of stratified medicines. From these reviews 165 primary economic evaluations of test-treat strategies were identified (from 2007 to 2010). Of these, 30 (18%) evaluations discussed potential capacity issues: limited health budgets; lack of quality laboratory and testing processes; ease of use of the test and results; and need for clinical and economic evidence in implementation. Methods used to account for capacity constraints included: capturing inefficiencies in trials or models; sensitivity analysis; and scenario analysis. Capacity constraints may impact the short-term cost-effectiveness of stratified medicines but few economic evaluations account for such constraints. Methodological developments are needed to take account of capacity constraints such as dynamic cost-effectiveness models or value of implementation analysis.

Clozapine induced gastrointestinal hypomotility: A potentially life threatening adverse event. A review of the literature.

The haematological and cardiac complications of clozapine have been well documented. Recent evidence from pharmacovigilance databases suggests that gastrointestinal (GI) complications are the leading cause of clozapine related deaths. This review aims to describe clinical features along with preventative and treatment options. A review of MEDLINE via PubMed searching for all articles published up to February of 2016. Inclusion criteria were articles that provided clinical or epidemiological information relating to the diagnosis, outcome, management or pathophysiology of clozapine related gastrointestinal disorders in humans. Three large case series were identified with 104 cases, 20 of these reported clinical details. A further 52 cases reports were included. Median age was 40, with 79% being male, mean daily clozapine dose was 453 mg. Mortality was 38% with survivors being younger (39 vs. 42), on lower daily doses (400 mg vs. 532 mg), more likely to be female (32% vs. 6%). Four patients were re-challenged with clozapine following CIGH, two suffered a recurrence. Risk factors for CIGH appear to be older age, male gender, patients in the first four months of treatment, co-prescription of constipating agents, higher daily dose of clozapine, and previous CIGH. Risk factors for death were older age and male gender. Patients receiving clozapine should be counselled about the dangers of constipation and to report new GI symptoms. Once severe CIGH has occurred clozapine should be halted and reviewed with bowel symptoms managed promptly. Re-challenging with clozapine may present substantial risks due to the severity of CIGH and a paucity of evidence. From the available evidence a treatment strategy has been proposed. Further prospective data regarding CIGH are needed to allow a better assessment of the scale of the problem with the development and testing of treatment strategies.

Research waste in diagnostic trials: a methods review evaluating the reporting of test-treatment interventions

BackgroundThe most rigorous method for evaluating the effectiveness of diagnostic tests is through randomised trials that compare test-treatment interventions: complex interventions comprising episodes of testing, decision-making and treatment. The multi-staged nature of these interventions, combined with the need to relay diagnostic decision-making and treatment planning, has led researchers to hypothesise that test-treatment strategies may be very challenging to document. However, no reviews have yet examined the reporting quality of interventions used in test-treatment RCTs. In this study we evaluate the completeness of intervention descriptions in a systematically identified cohort of test-treatment RCTs.MethodsWe ascertained all test-treatment RCTs published 2004–2007, indexed in CENTRAL. Included trials randomized patients to diagnostic tests and measured patient outcomes after treatment. Two raters examined the completeness of test-treatment intervention descriptions in four components: 1) the test, 2) diagnostic decision-making, 3) management decision-making, 4) treatments.ResultsOne hundred and three trials compared 105 control with 119 experimental interventions, most commonly in cardiovascular medicine (35, 34%), obstetrics and gynecology (17%), gastroenterology (14%) or orthopedics (10%). A broad range of tests were evaluated, including imaging (50, 42%), biochemical assays (21%) and clinical assessment (12%). Only five (5%) trials detailed all four components of experimental and control interventions, none of which also provided a complete care pathway diagram. Experimental arms were missing descriptions of tests, diagnostic-decision making, management planning and treatments (36%, 51%, 55% and 79% of trials respectively); control arms were missing the same details in 61%, 66%, 67% and 84% of trials.ConclusionReporting of test-treatment interventions is very poor, inadequate for understanding the results of these trials, and for comparing or translating results into clinical practice. Reporting needs to improve, with greater emphasis on describing the decision-making components of care pathways in both pragmatic and explanatory trials.Please see the companion paper to this article: http://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-016-0287-z.

Test-treatment RCTs are susceptible to bias: a review of the methodological quality of randomized trials that evaluate diagnostic tests

BackgroundThere is a growing recognition for the need to expand our evidence base for the clinical effectiveness of diagnostic tests. Many international bodies are calling for diagnostic randomized controlled trials to provide the most rigorous evidence of impact to patient health. Although these so-called test-treatment RCTs are very challenging to undertake due to their methodological complexity, they have not been subjected to a systematic appraisal of their methodological quality. The extent to which these trials may be producing biased results therefore remains unknown. We set out to address this issue by conducting a methodological review of published test-treatment trials to determine how often they implement adequate methods to limit bias and safeguard the validity of results.MethodsWe ascertained all test-treatment RCTs published 2004–2007, indexed in CENTRAL, including RCTs which randomized patients to diagnostic tests and measured patient outcomes after treatment. Tests used for screening, monitoring or prognosis were excluded. We assessed adequacy of sequence generation, allocation concealment and intention-to-treat, appropriateness of primary analyses, blinding and reporting of power calculations, and extracted study characteristics including the primary outcome.ResultsOne hundred three trials compared 105 control with 119 experimental interventions, and reported 150 primary outcomes. Randomization and allocation concealment were adequate in 57 and 37% of trials. Blinding was uncommon (patients 5%, clinicians 4%, outcome assessors 21%), as was an adequate intention-to-treat analysis (29%). Overall 101 of 103 trials (98%) were at risk of bias, as judged using standard Cochrane criteria.ConclusionTest-treatment trials are particularly susceptible to attrition and inadequate primary analyses, lack of blinding and under-powering. These weaknesses pose much greater methodological and practical challenges to conducting reliable RCT evaluations of test-treatment strategies than standard treatment interventions. We suggest a cautious approach that first examines whether a test-treatment intervention can accommodate the methodological safeguards necessary to minimize bias, and highlight that test-treatment RCTs require different methods to ensure reliability than standard treatment trials.Please see the companion paper to this article: http://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-016-0286-0.

Influenza A virus in swine breeding herds: Combination of vaccination and biosecurity practices can reduce likelihood of endemic piglet reservoir

Recent modelling and empirical work on influenza A virus (IAV) suggests that piglets play an important role as an endemic reservoir. The objective of this study is to test intervention strategies aimed at reducing the incidence of IAV in piglets and ideally, preventing piglets from becoming exposed in the first place. These interventions include biosecurity measures, vaccination, and management options that swine producers may employ individually or jointly to control IAV in their herds. We have developed a stochastic Susceptible-Exposed-Infectious-Recovered-Vaccinated (SEIRV) model that reflects the spatial organization of a standard breeding herd and accounts for the different production classes of pigs therein. Notably, this model allows for loss of immunity for vaccinated and recovered animals, and for vaccinated animals to have different latency and infectious periods from unvaccinated animals as suggested by the literature. The interventions tested include: (1) varied timing of gilt introductions to the breeding herd, (2) gilt separation (no indirect transmission to or from the gilt development unit), (3) gilt vaccination upon arrival to the farm, (4) early weaning, and (5) vaccination strategies of sows with different timing (mass and pre-farrow) and efficacy (homologous vs. heterologous). We conducted a Latin Hypercube Sampling and Partial Rank Correlation Coefficient (LHS-PRCC) analysis combined with a random forest analysis to assess the relative importance of each epidemiological parameter in determining epidemic outcomes. In concert, mass vaccination, early weaning of piglets (removal 0–7days after birth), gilt separation, gilt vaccination, and longer periods between introductions of gilts (6 months) were the most effective at reducing prevalence. Endemic prevalence overall was reduced by 51% relative to the null case; endemic prevalence in piglets was reduced by 74%; and IAV was eliminated completely from the herd in 23% of all simulations. Importantly, elimination of IAV was most likely to occur within the first few days of an epidemic. The latency period, infectious period, duration of immunity, and transmission rate for piglets with maternal immunity had the highest correlation with three separate measures of IAV prevalence; therefore, these are parameters that warrant increased attention for obtaining empirical estimates. Our findings support other studies suggesting that piglets play a key role in maintaining IAV in breeding herds. We recommend biosecurity measures in combination with targeted homologous vaccination or vaccines that provide wider cross-protective immunity to prevent incursions of virus to the farm and subsequent establishment of an infected piglet reservoir.

Are Chinese pediatricians missing the opportunity to help parents quit smoking?

BackgroundSecondhand smoke (SHS) exposure of children due to parental tobacco use is a particularly prevalent health issue and is associated with adverse health outcomes. Following the US Clinical Practice guidelines, pediatricians in the United States deliver 5A’s (ask, advise, assess, assist, and arrange) counseling to smoking parents which has proven to be effective. We examined Chinese pediatricians’ adherence to the clinical practice guidelines for smoking cessation (i.e. 5A’s counseling practices) with smoking parents, and identified factors associated with these practices.MethodsA cross-sectional paper-and-pencil survey of pediatricians was conducted in twelve conveniently selected southern Chinese hospitals. Factors associated with any of the 5A’s smoking cessation counseling practices were identified by logistic regression.ResultsOf respondents (504/550), only 26 % routinely provided 5A’s smoking cessation counseling to smoking parents. More than 80 % of pediatricians didn’t receive formal training in smoking cessation and had not read China smoking cessation guidelines; 24 % reported being “very confident” in discussing smoking or SHS reduction with parents. Pediatricians who had never smoked (OR: 2.29, CI:1.02-5.12), received training in smoking cessation (OR: 2.50, CI:1.40-4.48), had read China smoking cessation guidelines (OR: 2.17, CI:1.10-4.26), and felt very (OR: 7.12, CI:2.45-20.70) or somewhat (OR: 3.05, CI:1.11-8.37) confident in delivering cessation counseling were more likely to practice 5A’s. Pediatricians who reported “it is hard to find a time to talk with parents” (OR: 0.32, CI: 0.11-0.92) or “lack of a standard of care requiring pediatricians to provide smoking cessation or SHS exposure reduction intervention” (OR: 0.45, CI: 0.21-0.98) as a barrier were less likely to follow the 5A’s guidelines.ConclusionsSmoking cessation counseling to address parental smoking is infrequent among Chinese pediatricians. There is a need to develop and test intervention strategies to improve the delivery of 5A’s smoking cessation counseling to parental smokers.

Abstract IA12: Addressing cervical cancer disparities in Appalachia: From biology to policy

Abstract IA12: Addressing cervical cancer disparities in Appalachia: From biology to policy

Contributions of Nonhuman Primates to Research on Aging.

Aging is the biological process of declining physiologic function associated with increasing mortality rate during advancing age. Humans and higher nonhuman primates exhibit unusually longer average life spans as compared with mammals of similar body mass. Furthermore, the population of humans worldwide is growing older as a result of improvements in public health, social services, and health care systems. Comparative studies among a wide range of organisms that include nonhuman primates contribute greatly to our understanding about the basic mechanisms of aging. Based on their genetic and physiologic relatedness to humans, nonhuman primates are especially important for better understanding processes of aging unique to primates, as well as for testing intervention strategies to improve healthy aging and to treat diseases and disabilities in older people. Rhesus and cynomolgus macaques are the predominant monkeys used in studies on aging, but research with lower nonhuman primate species is increasing. One of the priority topics of research about aging in nonhuman primates involves neurologic changes associated with cognitive decline and neurodegenerative diseases. Additional areas of research include osteoporosis, reproductive decline, caloric restriction, and their mimetics, as well as immune senescence and chronic inflammation that affect vaccine efficacy and resistance to infections and cancer. The purpose of this review is to highlight the findings from nonhuman primate research that contribute to our understanding about aging and health span in humans.

Opportunities for Improvement in the Care of Patients Hospitalized for Inflammatory Bowel Disease-Related Colitis.

Algorithms for the diagnosis, management, and follow-up have been proposed for patients hospitalized for inflammatory bowel disease (IBD) colitis flare. The degree to which providers adhere to these algorithms is unknown. This study evaluated the quality of care in IBD patients hospitalized for disease-associated exacerbations and factors correlated with higher degrees of care. Retrospective chart review of 34 patients during 60 admissions to the medicine service for IBD colitis exacerbation between 2005 and 2012 at the Veterans Affairs San Diego Medical Center. Examined factors included laboratory testing, timing of consultation and intravenous steroids, abdominal imaging, endoscopic examination, venous thromboembolism (VTE) prophylaxis, narcotic use, Clostridium difficile and cytomegalovirus testing, symptomatology at discharge, timing of follow-up, and rates of readmission and mortality. Quality of care varied among the factors studied, ranging from 30.5 % for pharmacologic VTE prophylaxis to 84.7 % for gastroenterology consultation within 24 h. Of 60 admissions, 22 % were not tested for C. difficile. Fifteen percent of patients were discharged before meeting commonly used discharge criteria. Eighty percent were seen in clinic at any time post-discharge; 6.7 % were readmitted; 10 % were lost to follow-up; 1.7 % opted for outside follow-up; and 1.7 % expired. The quality of care for patients admitted with IBD colitis flares is variable. These data outline opportunities for improvement, particularly in regard to pain management, VTE prophylaxis, and follow-up. Further studies are needed to test intervention strategies for practice improvement.

Hypertension and diabetes in Africa: design and implementation of a large population-based study of burden and risk factors in rural and urban Malawi.

BackgroundThe emerging burden of cardiovascular disease and diabetes in sub-Saharan Africa threatens the gains made in health by the major international effort to combat infectious diseases. There are few data on distribution of risk factors and outcomes in the region to inform an effective public health response. A comprehensive research programme is being developed aimed at accurately documenting the burden and drivers of NCDs in urban and rural Malawi; to design and test intervention strategies. The programme includes population surveys of all people aged 18 years and above, linking individuals with newly diagnosed hypertension and diabetes to healthcare and supporting clinical services. The successes, challenges and lessons learnt from the programme to date are discussed.ResultsOver 20,000 adults have been recruited in rural Karonga and urban Lilongwe. The urban population is significantly younger and wealthier than the rural population. Employed urban individuals, particularly males, give particular recruitment challenges; male participation rates were 80.3 % in the rural population and 43.6 % in urban, whilst female rates were 93.6 and 75.6 %, respectively. The study is generating high quality data on hypertension, diabetes, lipid abnormalities and risk factors.ConclusionsIt is feasible to develop large scale studies that can reliably inform the public health approach to diabetes, cardiovascular disease and other NCDs in Sub-Saharan Africa. It is essential for studies to capture both rural and urban populations to address disparities in risk factors, including age structure. Innovative approaches are needed to address the specific challenge of recruiting employed urban males.

Exploring the moderating effect of children's nutritional knowledge on the relationship between product evaluations and food choice

ObjectiveAlthough the last decade has seen multiple attempts to increase consumers' nutritional knowledge in expectation that this will result in healthier diets, extant knowledge about the influence of nutritional knowledge on children's food choices remains scarce due to mixed empirical evidence and limited inquiry into the role of product evaluations on the consumption of less healthy foods. Furthermore, no research has examined whether nutritional knowledge can effectively moderate the relationship between product evaluations and food consumption, leaving a gap in our knowledge about potentially effective intervention strategies to curb childhood obesity. MethodUsing survey data from children aged 7–13 years and their parents (N = 354) recruited at an annual fair visited by families in South Australia, regressions were performed to examine how product evaluations are associated with the consumption of less healthy foods and whether nutritional knowledge reduces the strength of these associations at different ages (7–8 years, 9–10 years, and 11–13 years). ResultsWhile children did not view fast foods to be fun or healthy, there was a positive association between appealing taste, perceived social acceptability and consumption of less healthy foods. Higher nutritional knowledge weakened the relationship between product evaluations and consumption in children younger than 11. Parents with higher nutritional knowledge had children who tended to consume less healthy foods less frequently. Although older children (11–13 years) possessed higher nutritional knowledge, it was not associated with their consumption; instead, taste and perception of social acceptability were the only factors associated with frequent consumption of less healthy products. ConclusionPractitioners are encouraged to test intervention strategies that concentrate on both product evaluations and nutritional knowledge to provide more effective outcomes. Further research about peer norms that endorse unhealthy eating is encouraged to facilitate a more comprehensive approach to unhealthy eating.

Cost effectiveness of personalized treatment in women with early breast cancer: the application of OncotypeDX and Adjuvant! Online to guide adjuvant chemotherapy in Austria.

A Breast Cancer Outcomes model was developed at the ONCOTYROL research center to evaluate personalized test-treatment strategies in Austria. The goal was to evaluate the cost-effectiveness of a new 21-gene assay (ODX) when used in conjunction with the Adjuvant! Online (AO) decision aid to support personalized decisions about use of adjuvant chemotherapy in early-stage breast cancer patients in Austria. We applied a validated discrete-event-simulation model to a hypothetical cohort of 50 years old women over a lifetime horizon. The test-treatment strategies of interest were defined using three-letter acronyms. The first (second, third) letter indicates whether patients with a low (intermediate, high) risk according to AO were tested using ODX (Y yes, N no). The main outcomes were life-years gained, quality-adjusted life-years (QALYs), costs and cost effectiveness. Robustness of the results was tested in sensitivity analyses. Results were compared to a Canadian analysis conducted by the Toronto Health Economics and Technology Assessment Collaborative (THETA). Five of eight strategies were dominated (i.e., more costly and less effective: NNY, NYN, YNN, YNY, YYN). The base-case analysis shows that YYY (ODX provided to all patients) is the most effective strategy and is cost effective with an incremental cost-effectiveness ratio of 15,700 EUR per QALY gained. These results are sensitive to changes in the probabilities of distant recurrence, age and costs of chemotherapy. The results of the base-case analysis were comparable to the THETA results. Based on our analyses, using ODX in addition to AO is effective and cost effective in all women in Austria. The development of future genetic tests may require alternative or additional test-treatment strategies to be evaluated.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1440-6) contains supplementary material, which is available to authorized users.

Barriers to blinding: an analysis of the feasibility of blinding in test-treatment RCTS

Test-treatment strategies are complex interventions involving four main ingredients: 1) testing, 2) diagnostic decision-making, 3) therapeutic decision-making, 4) subsequent treatment. Methodologists have argued that it may be impossible to control for performance bias when evaluating these strategies using RCTs, since test results must be used by clinicians to plan patient management, whilst patients are often actively involved in testing processes and treatment selection. Analysis of complex therapeutic interventions has shown blinding is not always feasible, however claims regarding the ability to blind in test-treatment trials have not been evaluated. This methodological review analysed a systematically-derived cohort of 103 test-treatment trials to determine the frequency of blinding, and feasibility of blinding care-providers, patients and outcome assessors. Judgments of feasibility were based on subjective assessments following previously published methods. Care-providers, patients and outcome assessors were masked by 4%, 5% and 22% of trials, and could have been masked by a total of 11%, 50% and 66% respectively. Scarcity of attempts to blind reflected the practical and ethical difficulties in performing sham diagnostic procedures, or masking real test results from patients and clinicians. Feasibility hinged on: the types of tests, nature of their comparison, type of information produced and circumstances surrounding their administration. These findings present worrying implications for the validity of test-treatment RCTs. Unexpectedly we found that in some circumstances blinding may alter or eliminate the desired test-treat effect, and recommend further investigation to determine the true impact of masking in these highly complicated trials.

Lessons Learned from a Cross-Model Validation between a Discrete Event Simulation Model and a Cohort State-Transition Model for Personalized Breast Cancer Treatment.

Breast cancer is the most common malignancy among women in developed countries. We developed a model (the Oncotyrol breast cancer outcomes model) to evaluate the cost-effectiveness of a 21-gene assay when used in combination with Adjuvant! Online to support personalized decisions about the use of adjuvant chemotherapy. The goal of this study was to perform a cross-model validation. The Oncotyrol model evaluates the 21-gene assay by simulating a hypothetical cohort of 50-year-old women over a lifetime horizon using discrete event simulation. Primary model outcomes were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). We followed the International Society for Pharmacoeconomics and Outcomes Research-Society for Medical Decision Making (ISPOR-SMDM) best practice recommendations for validation and compared modeling results of the Oncotyrol model with the state-transition model developed by the Toronto Health Economics and Technology Assessment (THETA) Collaborative. Both models were populated with Canadian THETA model parameters, and outputs were compared. The differences between the models varied among the different validation end points. The smallest relative differences were in costs, and the greatest were in QALYs. All relative differences were less than 1.2%. The cost-effectiveness plane showed that small differences in the model structure can lead to different sets of nondominated test-treatment strategies with different efficiency frontiers. We faced several challenges: distinguishing between differences in outcomes due to different modeling techniques and initial coding errors, defining meaningful differences, and selecting measures and statistics for comparison (means, distributions, multivariate outcomes). Cross-model validation was crucial to identify and correct coding errors and to explain differences in model outcomes. In our comparison, small differences in either QALYs or costs led to changes in ICERs because of changes in the set of dominated and nondominated strategies.

The SPIRIT Action Framework: A structured approach to selecting and testing strategies to increase the use of research in policy

The recent proliferation of strategies designed to increase the use of research in health policy (knowledge exchange) demands better application of contemporary conceptual understandings of how research shapes policy. Predictive models, or action frameworks, are needed to organise existing knowledge and enable a more systematic approach to the selection and testing of intervention strategies. Useful action frameworks need to meet four criteria: have a clearly articulated purpose; be informed by existing knowledge; provide an organising structure to build new knowledge; and be capable of guiding the development and testing of interventions. This paper describes the development of the SPIRIT Action Framework. A literature search and interviews with policy makers identified modifiable factors likely to influence the use of research in policy. An iterative process was used to combine these factors into a pragmatic tool which meets the four criteria. The SPIRIT Action Framework can guide conceptually-informed practical decisions in the selection and testing of interventions to increase the use of research in policy.The SPIRIT Action Framework hypothesises that a catalyst is required for the use of research, the response to which is determined by the capacity of the organisation to engage with research. Where there is sufficient capacity, a series of research engagement actions might occur that facilitate research use. These hypotheses are being tested in ongoing empirical work.

The prognostic utility of tests of platelet function for the detection of 'aspirin resistance' in patients with established cardiovascular or cerebrovascular disease: a systematic review and economic evaluation.

The use of aspirin is well established for secondary prevention of cardiovascular disease. However, a proportion of patients suffer repeat cardiovascular events despite being prescribed aspirin treatment. It is uncertain whether or not this is due to an inherent inability of aspirin to sufficiently modify platelet activity. This report aims to investigate whether or not insufficient platelet function inhibition by aspirin ('aspirin resistance'), as defined using platelet function tests (PFTs), is linked to the occurrence of adverse clinical outcomes, and further, whether or not patients at risk of future adverse clinical events can be identified through PFTs. To review systematically the clinical effectiveness and cost-effectiveness evidence regarding the association between PFT designation of 'aspirin resistance' and the risk of adverse clinical outcome(s) in patients prescribed aspirin therapy. To undertake exploratory model-based cost-effectiveness analysis on the use of PFTs. Bibliographic databases (e.g. MEDLINE from inception and EMBASE from 1980), conference proceedings and ongoing trial registries up to April 2012. Standard systematic review methods were used for identifying clinical and cost studies. A risk-of-bias assessment tool was adapted from checklists for prognostic and diagnostic studies. (Un)adjusted odds and hazard ratios for the association between 'aspirin resistance', for different PFTs, and clinical outcomes are presented; however, heterogeneity between studies precluded pooling of results. A speculative economic model of a PFT and change of therapy strategy was developed. One hundred and eight relevant studies using a variety of PFTs, 58 in patients on aspirin monotherapy, were analysed in detail. Results indicated that some PFTs may have some prognostic utility, i.e. a trend for more clinical events to be associated with groups classified as 'aspirin resistant'. Methodological and clinical heterogeneity prevented a quantitative summary of prognostic effect. Study-level effect sizes were generally small and absolute outcome risk was not substantially different between 'aspirin resistant' and 'aspirin sensitive' designations. No studies on the cost-effectiveness of PFTs for 'aspirin resistance' were identified. Based on assumptions of PFTs being able to accurately identify patients at high risk of clinical events and such patients benefiting from treatment modification, the economic model found that a test-treat strategy was likely to be cost-effective. However, neither assumption is currently evidence based. Poor or incomplete reporting of studies suggests a potentially large volume of inaccessible data. Analyses were confined to studies on patients prescribed aspirin as sole antiplatelet therapy at the time of PFT. Clinical and methodological heterogeneity across studies precluded meta-analysis. Given the lack of robust data the economic modelling was speculative. Although evidence indicates that some PFTs may have some prognostic value, methodological and clinical heterogeneity between studies and different approaches to analyses create confusion and inconsistency in prognostic results, and prevented a quantitative summary of their prognostic effect. Protocol-driven and adequately powered primary studies are needed, using standardised methods of measurements to evaluate the prognostic ability of each test in the same population(s), and ideally presenting individual patient data. For any PFT to inform individual risk prediction, it will likely need to be considered in combination with other prognostic factors, within a prognostic model. This study is registered as PROSPERO 2012:CRD42012002151. The National Institute for Health Research Health Technology Assessment programme.

Cost-effectiveness analysis of cervical length measurement and fibronectin testing in women with threatened preterm labor

The objective of the study was to evaluate the cost-effectiveness of risk stratification with cervical length (CL) measurement and/or fetal fibronectin (fFN) tests in women with threatened preterm labor between 24 and 34 weeks' gestation. We performed a model-based cost-effectiveness analysis to evaluate 7 test-treatment strategies in women with threatened preterm labor from a health care system perspective. Estimates on disease prevalence, costs, and test accuracy were based on medical literature. We found that additional fFN testing in the case of a CL between 10 and 30 mm is cost saving without compromising neonatal health outcomes, compared with a treat-all strategy or single CL testing. Implementing this strategy could lead to an annual cost saving between €2.8 million and €14.4 million in The Netherlands, a country with about 180,000 deliveries annually. In women with threatened preterm labor between 24 and 34 weeks of gestation, the most cost-effective test strategy uses a combination of CL and fFN testing.

58P - Evaluation of Breast Cancer Test-Treatment Strategies Using Decision-Analytic Modeling – Preliminary Results for the 21-Gene Assay Recurrence Score

Objectives: Decision-analytic modeling can be used to evaluate short- and long term benefits, risks, harms and costs of new tests or treatments. At the ONCOTYROL research center, a Breast Cancer Outcomes model was developed to evaluate the cost effectiveness of personalized test-treatment strategies in Austria. The goal was to evaluate the cost effectiveness of the new 21-gene assay (OncotypeDX®) when it is applied in addition to the Adjuvant! Online® (AOL) decision aid to support personalized decisions on adjuvant chemotherapy.Methods: We developed a computer model to simulate a hypothetical cohort of 50 year old women over a lifetime using a discrete event simulation. The main outcomes were life-years gained, quality-adjusted life-years (QALYs), costs and cost-effectiveness. Based on the new ISPOR-SMDM recommendations, the model was validated. Eight test-treatment strategies were evaluated. Each strategy was defined by 3 letters. The first letter indicates whether patients with a low AOL risk were tested using OncotypeDX® (Y-yes; N-no), the second and the third letters provide this information for AOL intermediate and high-risk patients, respectively. Robustness of the results was tested in a sensitivity analysis. Results were compared to a Canadian analysis by the Toronto Health Economics and Technology Assessment Collaborative (THETA).Results: Five out of eight strategies were dominated (i.e. more costly and less effective: NNY, NYN, YNN, YNY, YYN). The base-case analysis shows that only the strategies in which OncotypeDX® is provided to patients with an intermediate or high AOL risk (incremental cost-effectiveness ratio (ICER) NYY = 1,600 €/QALY) and where all patients get OncotypeDX ®(ICER YYY 15,700 €/QALY) are cost effective. These results are sensitive to changes e.g in the probabilities of distant recurrence and age. The base case analysis was comparable to the THETA results.Conclusions: We showed that OncotypeDX®, when used in addition to the AOL, is cost effective in two test-treatment strategies (NYY, YYY) in Austria. Our simulation tool provides the flexibility to evaluate combinations of two or more tests that and respective treatment.Disclosure: All authors have declared no conflicts of interest. Objectives: Decision-analytic modeling can be used to evaluate short- and long term benefits, risks, harms and costs of new tests or treatments. At the ONCOTYROL research center, a Breast Cancer Outcomes model was developed to evaluate the cost effectiveness of personalized test-treatment strategies in Austria. The goal was to evaluate the cost effectiveness of the new 21-gene assay (OncotypeDX®) when it is applied in addition to the Adjuvant! Online® (AOL) decision aid to support personalized decisions on adjuvant chemotherapy. Methods: We developed a computer model to simulate a hypothetical cohort of 50 year old women over a lifetime using a discrete event simulation. The main outcomes were life-years gained, quality-adjusted life-years (QALYs), costs and cost-effectiveness. Based on the new ISPOR-SMDM recommendations, the model was validated. Eight test-treatment strategies were evaluated. Each strategy was defined by 3 letters. The first letter indicates whether patients with a low AOL risk were tested using OncotypeDX® (Y-yes; N-no), the second and the third letters provide this information for AOL intermediate and high-risk patients, respectively. Robustness of the results was tested in a sensitivity analysis. Results were compared to a Canadian analysis by the Toronto Health Economics and Technology Assessment Collaborative (THETA). Results: Five out of eight strategies were dominated (i.e. more costly and less effective: NNY, NYN, YNN, YNY, YYN). The base-case analysis shows that only the strategies in which OncotypeDX® is provided to patients with an intermediate or high AOL risk (incremental cost-effectiveness ratio (ICER) NYY = 1,600 €/QALY) and where all patients get OncotypeDX ®(ICER YYY 15,700 €/QALY) are cost effective. These results are sensitive to changes e.g in the probabilities of distant recurrence and age. The base case analysis was comparable to the THETA results. Conclusions: We showed that OncotypeDX®, when used in addition to the AOL, is cost effective in two test-treatment strategies (NYY, YYY) in Austria. Our simulation tool provides the flexibility to evaluate combinations of two or more tests that and respective treatment. Disclosure: All authors have declared no conflicts of interest.

Troubleshooting the rat model of cardiopulmonary bypass: Effects of avoiding blood transfusion on long-term survival, inflammation and organ damage

IntroductionRat models of cardiopulmonary bypass (CPB) have been used to examine the mechanisms of associated organ damage and to test intervention strategies. However, these models only partly mimic the clinical situation, because of the use of blood transfusion and arterial inflow via the tail artery. Thus a model using arterial inflow in the aorta and a miniaturized CPB circuit without need of transfusion was validated by examining intra-procedure characteristics, mortality and the effects of CPB on biomarkers of inflammation and cerebral injury during 5days follow-up. MethodsMale Wistar rats (n=95) were anesthetized with isoflurane (2.5%) and fentanyl/midazolam during CPB. Animals were assigned to Control (n=6), Sham (n=40) or normothermic CPB (n=49) groups. Both Sham and CPB were cannulated in the aorta via the left carotid artery and in the right common jugular vein for access into the right heart. Extracorporeal circulation (ECC) was instituted for 60min only in CPB at a flow rate of 120mLkg−1min−1 employing a CPB circuit of 15ml primed with 6% hydroxyethyl starch 60mgml−1 solution. Rats were sacrificed at either 1h or 1, 2 or 5days after Sham or weaning from CPB. Plasma IL-6 and s100Beta levels were measured and blood cell counts were performed. ResultsMortality in CPB animals (3 out of 49) and Sham (4 out of 40) did not differ (chi-square=0.46, dF=1, P>0.5). Compared to baseline (1.87±0.46∗10^9cells/L), Sham procedure (cannulation and anesthesia) significantly increased blood neutrophil count at the end of the period matching ECC (6.34±2.36∗10^9cells/L, P<0.05). CPB induced neutrophilia which persisted during 24h recovery. Also, CPB caused a rapid and prominent increase in plasma IL-6 from the first hour of the postoperative period (~1200pg/ml) with continuation (50–90pg/ml) up to 5th day of recovery. S100Beta levels were above detection level only in 3 out of 42 samples from CPB animals. DiscussionOur rat model of CPB without homologous blood transfusion produces a reproducible and reliable systemic inflammatory response, with low mortality rates on long term follow up. The model more closely mimics the human situation in respect to arterial inflow site and avoidance of blood transfusion. Thus, our CPB model is suitable to study its influence on systemic inflammation, ischemia–reperfusion injury, microcirculation and vascular dysfunction in vivo, and to evaluate potential therapeutic interventions.

Hypercholesterolemia Promotes an Osteoporotic Phenotype

A role for hypercholesterolemia in the development of osteoporosis has been suggested in published reports. However, few studies contain direct evidence of a role for maintenance of cholesterol homeostasis in bone health. Using isocaloric high-fat/high-cholesterol and low-fat/no-cholesterol diets in a 4-month feeding study combined with micro computed tomography analysis, we demonstrated in two different mouse strains that mice with hypercholesterolemia lose cortical and trabecular bone in the femurs and vertebrae (bone mineral density was decreased on average by ≈90 mg/mL in the cortical vertebrae in one strain) and cortical bone in the calvariae (bone mineral density was decreased on average by ≈60 mg/mL in one strain). Mechanical testing of the femurs demonstrated that loss of bone in the mice with hypercholesterolemia caused changes in the mechanical properties of the bone including loss of failure load (failure load was decreased by ≈10 N in one strain) and energy to failure. Serologic and histomorphologic analyses suggested that hypercholesterolemia promotes osteoclastogenesis. These studies support a role for hypercholesterolemia in the development of osteoporosis and provide a model with which to test intervention strategies to reduce the effects of hypercholesterolemia on bone health.