Evidence used in model-based economic evaluations for evaluating pharmacogenetic and pharmacogenomic tests: a systematic review protocol

This is the final version of the article. Available from BMJ Publishing Grou via the DOI in this record.INTRODUCTION: Decision models can be used to conduct economic evaluations of new pharmacogenetic and pharmacogenomic tests to ensure they offer value for money to healthcare systems. These models require a great deal of evidence, yet research suggests the evidence used is diverse and of uncertain quality. By conducting a systematic review, we aim to investigate the test-related evidence used to inform decision models developed for the economic evaluation of genetic tests. METHODS AND ANALYSIS: We will search electronic databases including MEDLINE, EMBASE and NHS EEDs to identify model-based economic evaluations of pharmacogenetic and pharmacogenomic tests. The search will not be limited by language or date. Title and abstract screening will be conducted independently by 2 reviewers, with screening of full texts and data extraction conducted by 1 reviewer, and checked by another. Characteristics of the decision problem, the decision model and the test evidence used to inform the model will be extracted. Specifically, we will identify the reported evidence sources for the test-related evidence used, describe the study design and how the evidence was identified. A checklist developed specifically for decision analytic models will be used to critically appraise the models described in these studies. Variations in the test evidence used in the decision models will be explored across the included studies, and we will identify gaps in the evidence in terms of both quantity and quality. DISSEMINATION: The findings of this work will be disseminated via a peer-reviewed journal publication and at national and international conferences.JLP is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula and CC is funded by an NIHR Health Technology Assessment Grant (RNC-023-09)

The medium-term sustainability of organisational innovations in the national health service

Background: There is a growing recognition of the importance of introducing new ways of working into the UK's National Health Service (NHS) and other health systems, in order to ensure that patient care is provided as effectively and efficiently as possible. Researchers have examined the challenges of introducing new ways of working-'organisational innovations'-into complex organisations such as the NHS, and this has given rise to a much better understanding of how this takes place-and why seemingly good ideas do not always result in changes in practice. However, there has been less research on the medium-and longer-term outcomes for organisational innovations and on the question of how new ways of working, introduced by frontline clinicians and managers, are sustained and become established in day-to-day practice. Clearly, this question of sustainability is crucial if the gains in patient care that derive from organisational innovations are to be maintained, rather than lost to what the NHS Institute has called the 'improvement-evaporation effect'. Methods: The study will involve research in four case-study sites around England, each of which was successful in sustaining its new model of service provision beyond an initial period of pilot funding for new genetics services provided by the Department of Health. Building on findings relating to the introduction and sustainability of these services already gained from an earlier study, the research will use qualitative methods-in-depth interviews, observation of key meetings, and analysis of relevant documents-to understand the longer-term challenges involved in each case and how these were surmounted. The research will provide lessons for those seeking to sustain their own organisational innovations in wide-ranging clinical areas and for those designing the systems and organisations that make up the NHS, to make them more receptive contexts for the sustainment of innovation. Discussion: Through comparison and contrast across four sites, each involving different organisational innovations, different forms of leadership, and different organisational contexts to contend with, the findings of the study will have wide relevance. The research will produce outputs that are useful for managers and clinicians responsible for organisational innovation, policy makers and senior managers, and academics

“SQiD, the Single Question in Delirium; can a single question help clinicians to detect delirium in hospitalised cancer patients?” running heading Single Question in Delirium” (Bcan-D-20-01665)

AimA serious syndrome for cancer in-patients, delirium risk increases with age and medical acuity. Screening tools exist but detection is frequently delayed or missed. We test the 'Single Question in Delirium' (SQiD), in comparison to psychiatrist clinical interview.MethodsInpatients in two comprehensive cancer centres were prospectively screened. Clinical staff asked informants to respond to the SQiD: "Do you feel that [patient's name] has been more confused lately?". The primary endpoint was negative predictive value (NPV) of the SQiD versus psychiatrist diagnosis (Diagnostic and Statistics Manual criteria). Secondary endpoints included: NPV of the Confusion Assessment Method (CAM), sensitivity, specificity and Cohen's Kappa coefficient.ResultsBetween May 2012 and July 2015, the SQiD plus CAM was applied to 122 patients; 73 had the SQiD and psychiatrist interview. Median age was 65 yrs. (interquartile range 54-74), 46% were female; median length of hospital stay was 12 days (5-18 days). Major cancer types were lung (19%), gastric or other upper GI (15%) and breast (14%). 70% of participants had stage 4 cancer. Diagnostic values were similar between the SQiD (NPV = 74, 95% CI 67-81; kappa = 0.32) and CAM (NPV = 72, 95% CI 67-77, kappa = 0.32), compared with psychiatrist interview. Overall the CAM identified only a small number of delirious cases but all were true positives. The specificity of the SQiD was 87% (74-95) The SQiD had higher sensitivity than CAM (44% [95% CI 41-80] vs 26% [10-48]).ConclusionThe SQiD, administered by bedside clinical staff, was feasible and its psychometric properties are now better understood. The SQiD can contribute to delirium detection and clinical care for hospitalised cancer patients

Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

MSH3 gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as “elevated microsatellite alterations at selected tetranucleotide repeats” (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for MSH3, MCC, CDKN2A (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with ≥3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated. © 2012 Cicek et al

An Assessment of the Impact of Hafting on Paleoindian Point Variability

It has long been argued that the form of North American Paleoindian points was affected by hafting. According to this hypothesis, hafting constrained point bases such that they are less variable than point blades. The results of several studies have been claimed to be consistent with this hypothesis. However, there are reasons to be skeptical of these results. None of the studies employed statistical tests, and all of them focused on points recovered from kill and camp sites, which makes it difficult to be certain that the differences in variability are the result of hafting rather than a consequence of resharpening. Here, we report a study in which we tested the predictions of the hafting hypothesis by statistically comparing the variability of different parts of Clovis points. We controlled for the potentially confounding effects of resharpening by analyzing largely unused points from caches as well as points from kill and camp sites. The results of our analyses were not consistent with the predictions of the hypothesis. We found that several blade characters and point thickness were no more variable than the base characters. Our results indicate that the hafting hypothesis does not hold for Clovis points and indicate that there is a need to test its applicability in relation to post-Clovis Paleoindian points

Studying animal innovation at the individual level: a ratings-based assessment in capuchin monkeys (Sapajus [Cebus] sp.)

Large-scale studies of individual differences in animal innovation are rare firstly because discovery behaviour itself is often rare, and secondly because of logistical difficulties associated with obtaining observational data on a large number of innovative individuals across multiple groups and locations. Here we take a different approach, using observer ratings to study innovative behaviour in 127 brown capuchin monkeys (Sapajus [Cebus] sp.) from 15 social groups and 7 facilities. Capuchins were reliably rated by 1 to 7 raters (mean 3.2 ± 1.6 raters/monkey) on a 7-point Likert scale for levels of innovative behaviour, task motivation, sociality, and dominance. In a subsample, we demonstrate these ratings are valid: rated innovation predicted performance on a learning task, rated motivation predicted participation in the task, rated dominance predicted social rank based on win/loss aggressive outcomes, and rated sociality predicted the time that monkeys spent in close proximity to others. Across all 127 capuchins, individuals that were rated as being more innovated were significantly younger, more social, and more motivated to engage in tasks. Sociality, task motivation, and age all had independent effects on innovativeness, whereas sex, dominance and group size were non-significant. Our findings are consistent with long-term behavioural observations of innovation in wild white-faced capuchins. Observer ratings may therefore be a valid tool for studies of animal innovation, and our findings highlight in particular several possible scenarios through which innovative behaviour might be selected for among capuchins