Can analyses of electronic patient records be independently and externally validated? The effect of statins on the mortality of patients with ischaemic heart disease: a cohort study with nested case-control analysis

Objective To conduct a fully independent and external validation of a research study based on one electronic health record database, using a different electronic database sampling the same population. Design Using the Clinical Practice Research Datalink (CPRD), we replicated a published investigation into the effects of statins in patients with ischaemic heart disease (IHD) by a different research team using QResearch. We replicated the original methods and analysed all-cause mortality using: (1) a cohort analysis and (2) a case-control analysis nested within the full cohort. Setting Electronic health record databases containing longitudinal patient consultation data from large numbers of general practices distributed throughout the UK. Participants CPRD data for 34 925 patients with IHD from 224 general practices, compared to previously published results from QResearch for 13 029 patients from 89 general practices. The study period was from January 1996 to December 2003. Results We successfully replicated the methods of the original study very closely. In a cohort analysis, risk of death was lower by 55% for patients on statins, compared with 53% for QResearch (adjusted HR 0.45, 95% CI 0.40 to 0.50; vs 0.47, 95% CI 0.41 to 0.53). In case-control analyses, patients on statins had a 31% lower odds of death, compared with 39% for QResearch (adjusted OR 0.69, 95% CI 0.63 to 0.75; vs OR 0.61, 95% CI 0.52 to 0.72). Results were also close for individual statins. Conclusions Database differences in population characteristics and in data definitions, recording, quality and completeness had a minimal impact on key statistical outputs. The results uphold the validity of research using CPRD and QResearch by providing independent evidence that both datasets produce very similar estimates of treatment effect, leading to the same clinical and policy decisions. Together with other non-independent replication studies, there is a nascent body of evidence for wider validity

The role of the exit in the initial screening of investment opportunities: The case of business angel syndicate gatekeepers

The exit process has been largely ignored in business angel research.. The practitioner community identifies the difficulty in achieving exits as the most pressing problem for investors. This has been attributed to the failure of investors to adopt an exit-centric approach to investing. The validity of this claim is examined via a study of the investment approach of 21 ‘gatekeepers’ (managers) of angel groups in Scotland and Northern Ireland. Most gatekeepers say that they do consider the exit when they invest. However, this is contradicted by a verbal protocol analysis which indicates that the exit is not a significant consideration in their initial screening process. The small number of exits achieved by the groups is consistent with the general lack of an exit-centric approach to investing. Only three groups exhibit evidence of a strong exit-centric approach to investing. The lack of exits may have a negative impact on the level of future angel investment activity

Imaging endpoints for clinical trials in Alzheimer's disease

As the need to develop a successful disease-modifying treatment for Alzheimer's disease (AD) becomes more urgent, imaging is increasingly used in therapeutic trials. We provide an overview of how the different imaging modalities are used in AD studies and the current regulatory guidelines for their use in clinical trials as endpoints. We review the current literature for results of imaging endpoints of efficacy and safety in published clinical trials. We start with trials in mild to moderate AD, where imaging (largely magnetic resonance imaging (MRI)) has long played a role in inclusion and exclusion criteria; more recently, MRI has been used to identify adverse events and to measure rates of brain atrophy. The advent of amyloid imaging using positron emission tomography has led to trials incorporating amyloid measurements as endpoints and incidentally to the recognition of the high proportion of amyloid-negative individuals that may be recruited into these trials. Ongoing and planned trials now commonly include multimodality imaging: amyloid positron emission tomography, MRI and other modalities. At the same time, the failure of recent large profile trials in mild to moderate AD together with the realisation that there is a long prodromal period to AD has driven a push to move studies to earlier in the disease. Imaging has particularly important roles, alongside other biomarkers, in assessing efficacy because conventional clinical outcomes may have limited ability to detect treatment effects in these early stages

A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies

A promising direction in drug development is to exploit the ability of natural killer cells to kill antibody-labeled target cells. Monoclonal antibodies and drugs designed to elicit this effect typically bind cell-surface epitopes that are overexpressed on target cells but also present on other cells. Thus it is important to understand adhesion of cells by antibodies and similar molecules. We present an equilibrium model of such adhesion, incorporating heterogeneity in target cell epitope density and epitope immobility. We compare with experiments on the adhesion of Jurkat T cells to bilayers containing the relevant natural killer cell receptor, with adhesion mediated by the drug alefacept. We show that a model in which all target cell epitopes are mobile and available is inconsistent with the data, suggesting that more complex mechanisms are at work. We hypothesize that the immobile epitope fraction may change with cell adhesion, and we find that such a model is more consistent with the data. We also quantitatively describe the parameter space in which binding occurs. Our results point toward mechanisms relating epitope immobility to cell adhesion and offer insight into the activity of an important class of drugs.Comment: 13 pages, 5 figure

An eye-movement study of relational memory in adults with Autism Spectrum Disorder

Persons with Autism Spectrum Disorder (ASD) demonstrate good memory for single items but difficulties remembering contextual information related to these items. Recently, we found compromised explicit but intact implicit retrieval of object-location information in ASD (Ring et al. 2015). Eye-movement data collected from a sub-sample of the participants are the focus of the current paper. At encoding, trial-by-trial viewing durations predicted subsequent retrieval success only in typically developing (TD) participants. During retrieval, TD compared to ASD participants looked significantly longer at previously studied objectlocations compared to alternative locations. These findings extend similar observations recently reported by Cooper et al. (2017a) and demonstrate that eye-movement data can shed important light on the source and nature of relational memory difficulties in ASD

Age-related hyperkyphosis, independent of spinal osteoporosis, is associated with impaired mobility in older community-dwelling women

While many assume hyperkyphosis reflects underlying spinal osteoporosis and vertebral fractures, our results suggest hyperkyphosis is independently associated with decreased mobility. Hyperyphosis is associated with slower Timed Up and Go performance times and may be a useful clinical marker signaling the need for evaluation of vertebral fracture and falling risk. While multiple studies have demonstrated negative effects of hyperkyphosis on physical function, none have disentangled the relationship between hyperkyphosis, impaired function, and underlying spinal osteoporosis. The purpose of this study is to determine whether kyphosis, independent of spinal osteoporosis, is associated with mobility on the Timed Up and Go, and to quantify effects of other factors contributing to impaired mobility. We used data for 3,108 community-dwelling women aged 55-80 years in the Fracture Intervention Trial. All participants had measurements of kyphosis, mobility time on the Timed Up and Go test, height, weight, total hip bone mineral density (BMD), grip strength, and vertebral fractures at baseline visits in 1993. Demographic characteristics included age and smoking status. We calculated mean Timed Up and Go time by quartile of kyphosis. Using multivariate linear regression, we estimated the independent association of kyphosis with mobility time, and quantified effects of other covariates on mobility. Mean mobility time increased from 9.3 s in the lowest to 10.1 s in the highest quartile of kyphosis. In a multivariate-adjusted model, mobility time increased 0.11 s (p = 0.02) for each standard deviation (11.9°) increase in kyphosis. Longer performance times were significantly associated with increasing age, decreasing grip strength, vertebral fractures, body mass index ≥25, and total hip BMD in the osteoporotic range. Kyphosis angle is independently associated with decreased mobility on the Timed Up and Go, which is in turn correlated with increased fall risk. Hyperkyphosis may be a useful clinical marker signaling the need for evaluation of vertebral fracture and falling risk

Mediated behavioural change in human-machine networks: exploring network characteristics, trust and motivation

Human-machine networks pervade much of contemporary life. Network change is the product of structural modifications along with differences in participant be-havior. If we assume that behavioural change in a human-machine network is the result of changing the attitudes of participants in the network, then the question arises whether network structure can affect participant attitude. Taking citizen par-ticipation as an example, engagement with relevant stakeholders reveals trust and motivation to be the major objectives for the network. Using a typology to de-scribe network state based on multiple characteristic or dimensions, we can pre-dict possible behavioural outcomes in the network. However, this has to be medi-ated via attitude change. Motivation for the citizen participation network can only increase in line with enhanced trust. The focus for changing network dynamics, therefore, shifts to the dimensional changes needed to encourage increased trust. It turns out that the coordinated manipulation of multiple dimensions is needed to bring about the desired shift in attitude.Comment: Paper submitted to SocInfo, organised by the Oxford Internet Institute, September 201

Branching on multi-aggregated variables

open5siopenGamrath, Gerald; Melchiori, Anna; Berthold, Timo; Gleixner, Ambros M.; Salvagnin, DomenicoGamrath, Gerald; Melchiori, Anna; Berthold, Timo; Gleixner, Ambros M.; Salvagnin, Domenic

The reliability and validity of three non-radiological measures of thoracic kyphosis and their relations to the standing radiological Cobb angle

UnlabelledHyperkyphosis is implicated in a mounting list of negative outcomes, including higher mortality. Hyperkyphosis research is hindered due to difficulties inherent in its measurement. By showing that three clinical measures of kyphosis are suitable for use in large scale, longitudinal, hyperkyphosis studies, we will facilitate much needed research in this field.IntroductionThe objective of this study is to describe the reliability of three non-radiological kyphosis measures (Debrunner kyphosis angle, flexicurve kyphosis index, and flexicurve kyphosis angle) and their validity compared to the Cobb angle and to approximate a Cobb angle from non-radiological kyphosis measures.MethodsWe analyzed data from 113 participants aged ≥ 60 years with kyphosis angle ≥ 40°. Cobb angle was measured on a standing lateral thoracolumbar radiograph using bounds at T4 and T12. Non-radiological measures of kyphosis were made three times by a single rater and a 4th time by a blinded second rater.ResultsIntra- and inter-rater reliabilities for non-radiological assessments were high (intra-class correlations of 0.96 to 0.98) and did not differ from each other. Pearson correlations, estimating validity, ranged from 0.62 to 0.69 and did not differ. The Debrunner angle was close to the Cobb angle, with scaling factor of 1.067 and an offset of 5°. The Flexicurve kyphosis angle had to be scaled by 1.53 to obtain the equivalent Cobb angle. The scaling factor for the Flexicurve kyphosis index to Cobb angle was 315, with an offset of 5°. Compared to the measured Cobb angle, Cobb angles predicted using the non-radiological measures had similar magnitude errors (standard deviations of the differences ranging between 10.24 and 11.26).ConclusionsEach non-radiological measurement had similar reliability and validity. Low cost, ease of use, and robustness to variations in spine contour argue for the Flexicurve in longitudinal kyphosis assessments. The approximate conversion factors provided will permit translation of non-radiological measures to Cobb angles