The protocol of a clinical effectiveness trial comparing standard step-up care, early combination DMARD therapy and early use of TNF inhibitors for the treatment of moderate to severe psoriatic arthritis: the 3-arm parallel group SPEED randomized controlled trial.

Objectives: The aim of the Severe Psoriatic arthritis - Early intervEntion to control Disease trial is to compare outcomes in psoriatic arthritis (PsA) patients with poor prognostic factors treated with standard step-up conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), combination csDMARDs or a course of early biologics. Design: This multicentre UK trial was embedded within the MONITOR-PsA cohort, which uses a trial within cohort design. Methods and analysis: Patients with newly diagnosed PsA and at least one poor prognostic factor (polyarthritis, C-reactive protein >5 mg/dL, health assessment questionnaire >1, radiographic erosions) were randomized equally and open-label to either standard care with 'step-up' csDMARD therapy, initial therapy with combination csDMARDs (methotrexate with either sulfasalazine or leflunomide) or to early biologics induction therapy (adalimumab plus methotrexate). The primary outcome is the PsA disease activity score at week 24. Ethics: Ethical approval for the study was granted by the South Central Research Ethics Committee (ref 18/SC/0107). Discussion: Treatment recommendations for PsA suggest more intensive therapy for those with poor prognostic factors but there are no studies that have previously used prognostic factors to guide therapy. Applying initial intensive therapy has shown improved outcomes in other inflammatory arthritides but has never been tried in PsA. Combination csDMARDs have shown some superiority over single therapies but there are limited data and concerns about side effects. Early use of biologics has also been shown to be superior to methotrexate but these drugs are costly and not usually funded first line. However, if a short course of biologics can rapidly suppress inflammation allowing treatment to be withdrawn and response maintained on methotrexate, this may be a cost-effective model for early use. Trial registration: ClinicalTrials.gov (NCT03739853) and EudraCT (2017-004542-24).

Anti-TNF (adalimumab) injection for the treatment of pain-predominant early-stage frozen shoulder: the Anti-Freaze-Feasibility randomised controlled trial.

OBJECTIVE: The Anti-Freaze-F (AFF) trial assessed the feasibility of conducting a definitive trial to determine whether intra-articular injection of adalimumab can reduce pain and improve function in people with pain-predominant early-stage frozen shoulder. DESIGN: Multicentre, randomised feasibility trial, with embedded qualitative study. SETTING: Four UK National Health Service (NHS) musculoskeletal and related physiotherapy services. PARTICIPANTS: Adults ≥18 years with new episode of shoulder pain attributable to early-stage frozen shoulder. INTERVENTIONS: Participants were randomised (centralised computer generated 1:1 allocation) to either ultrasound-guided intra-articular injection of: (1) adalimumab (160 mg) or (2) placebo (saline (0.9% sodium chloride)). Participants and outcome assessors were blinded to treatment allocation. Second injection of allocated treatment (adalimumab 80 mg) or equivalent placebo was administered 2-3 weeks later. PRIMARY FEASIBILITY OBJECTIVES: (1) Ability to screen and identify participants; (2) willingness of eligible participants to consent and be randomised; (3) practicalities of delivering the intervention; (4) SD of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months. RESULTS: Between 31 May 2022 and 7 February 2023, 156 patients were screened of whom 39 (25%) were eligible. The main reasons for ineligibility were other shoulder disorder (38.5%; n=45/117) or no longer in pain-predominant frozen shoulder (33.3%; n=39/117). Of the 39 eligible patients, nine (23.1%) consented to be randomised (adalimumab n=4; placebo n=5). The main reason patients declined was because they preferred receiving steroid injection (n=13). All participants received treatment as allocated. The mean time from randomisation to first injection was 12.3 (adalimumab) and 7.2 days (placebo). Completion rates for patient-reported and clinician-assessed outcomes were 100%. CONCLUSION: This study demonstrated that current NHS musculoskeletal physiotherapy settings yielded only small numbers of participants, too few to make a trial viable. This was because many patients had passed the early stage of frozen shoulder or had already formulated a preference for treatment. TRIAL REGISTRATION NUMBER: ISRCTN 27075727, EudraCT 2021-03509-23, ClinicalTrials.gov NCT05299242 (REC 21/NE/0214).

Cigarette smoking and risk of severe infectious respiratory diseases in UK adults: 12-year follow-up of UK biobank.

BACKGROUND: The relevance of tobacco smoking for infectious respiratory diseases (IRD) is uncertain. We investigated the associations of cigarette smoking with severe IRD resulting in hospitalization or death in UK adults. METHODS: We conducted a prospective study of cigarette smoking and risk of severe IRD in UK Biobank. The outcomes included pneumonia, other acute lower respiratory tract infections (OA-LRTI) and influenza. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) of severe IRD associated with smoking habits after adjusting for confounding factors. RESULTS: Among 341 352 participants with no prior history of major chronic diseases, there were 12 384 incident cases with pneumonia, 7054 with OA-LRTI and 795 with influenza during a 12-year follow-up. Compared with non-smokers, current smoking was associated with ⁓2-fold higher rates of severe IRD (HR 2.40 [2.27-2.53] for pneumonia, 1.99 [1.84-2.14] for OA-LRTI and 1.82 [95% confidence interval: 1.47-2.24] for influenza). Incidence of all severe IRDs were positively associated with amount of cigarettes smoked. The HRs for each IRD (except influenza) also declined with increasing duration since quitting. CONCLUSIONS: Current cigarette smoking was positively associated with higher rates of IRD and the findings extend indications for tobacco control measures and vaccination of current smokers for prevention of severe IRD.

Body Mass Index and Risk of Hospitalization or Death Due to Lower or Upper Respiratory Tract Infection.

This study assesses the associations between body mass index and risk of hospitalization for or death due to COVID-19, lower respiratory tract infections, and upper respiratory tract infections.

Systematic review of the utility of the frailty index and frailty phenotype to predict all-cause mortality in older people.

BACKGROUND: Current guidelines for healthcare of community-dwelling older people advocate screening for frailty to predict adverse health outcomes, but there is no consensus on the optimum instrument to use in such settings. The objective of this systematic review of population studies was to compare the ability of the frailty index (FI) and frailty phenotype (FP) instruments to predict all-cause mortality in older people. METHODS: Studies published before 27 July 2022 were identified using Ovid MEDLINE, Embase, Scopus, Web of Science and CINAHL databases. The eligibility criteria were population-based prospective studies of community-dwelling older adults (aged 65 years or older) and evaluation of both the FI and FP for prediction of all-cause mortality. The Scottish Intercollegiate Guidelines Network's Methodology checklist was used to assess study quality. The areas under the receiver operator characteristic curves (AUC) were compared, and the proportions of included studies that achieved acceptable discriminatory power (AUC>0.7) were calculated for each frailty instrument. The results were stratified by the use of continuous or categorical formats of each instrument. The review was reported in accordance with the PRISMA and SWiM guidelines. RESULTS: Among 8 studies (range: 909 to 7713 participants), both FI and FP had comparable predictive power for all-cause mortality. The AUC values ranged from 0.66 to 0.84 for FI continuous, 0.60 to 0.80 for FI categorical, 0.63 to 0.80 for FP continuous and 0.57 to 0.79 for FP categorical. The proportion of studies achieving acceptable discriminatory power were 75%, 50%, 63%, and 50%, respectively. The predictive ability of each frailty instrument was unaltered by the number of included items. CONCLUSIONS: Despite differences in their content, both the FI and FP instruments had modest but comparable ability to predict all-cause mortality. The use of continuous rather than categorical formats in either instrument enhanced their ability to predict all-cause mortality.

Development of a Model to Predict 10-Year Risk of Ischemic and Hemorrhagic Stroke and Ischemic Heart Disease Using the China Kadoorie Biobank.

BACKGROUND AND OBJECTIVES: Contemporary cardiovascular disease (CVD) risk prediction models are rarely applied in routine clinical practice in China due to substantial regional differences in absolute risks of major CVD types within China. Moreover, the inclusion of blood lipids in most risk prediction models also limits their use in the Chinese population. We developed 10-year CVD risk prediction models excluding blood lipids that may be applicable to diverse regions of China. METHODS: We derived sex-specific models separately for ischemic heart disease (IHD), ischemic stroke (IS), and hemorrhagic stroke (HS) in addition to total CVD in the China Kadoorie Biobank. Participants were age 30-79 years without CVD at baseline. Predictors included age, systolic and diastolic blood pressure, use of blood pressure-lowering treatment, current daily smoking, diabetes, and waist circumference. Total CVD risks were combined in terms of conditional probability using the predicted risks of 3 submodels. Risk models were recalibrated in each region by 2 methods (practical and ideal) and risk prediction was estimated before and after recalibration. RESULTS: Model derivation involved 489,596 individuals, including 45,947 IHD, 43,647 IS, and 11,168 HS cases during 11 years of follow-up. In women, the Harrell C was 0.732 (95% CI 0.706-0.758), 0.759 (0.738-0.779), and 0.803 (0.778-0.827) for IHD, IS, and HS, respectively. The Harrell C for total CVD was 0.734 (0.732-0.736), 0.754 (0.752-0.756), and 0.774 (0.772-0.776) for models before recalibration, after practical recalibration, and after ideal recalibration. The calibration performances improved after recalibration, with models after ideal recalibration showing the best model performances. The results for men were comparable to those for women. DISCUSSION: Our CVD risk prediction models yielded good discrimination of IHD and stroke subtypes in addition to total CVD without including blood lipids. Flexible recalibration of our models for different regions could enable more widespread use using resident health records covering the overall Chinese population. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a prediction model incorporating accessible clinical variables predicts 10-year risk of IHD, IS, and HS in the Chinese population age 30-79 years.

Variability and agreement of frailty measures and risk of falls, hospital admissions and mortality in TILDA.

Little is known about the within-person variability of different frailty instruments, their agreement over time, and whether use of repeat assessments could improve the strength of associations with adverse health outcomes. Repeat measurements recorded in 2010-2011 (Wave 1) and 2012 (Wave 2) from The Irish Longitudinal Study on Ageing (TILDA) were used to classify individuals with frailty using the frailty phenotype (FP) and frailty index (FI). Within-person variability and agreement of frailty classifications were assessed using ANOVA and kappa (K) statistics, respectively. Associations of each frailty measure (wave 1, wave 2, or mean of both waves) with risk of falls, hospitalisations and all-cause mortality were assessed using logistic regression. Among 7455 individuals (mean age 64.7 [SD 9.9] years), within-person SD was 0.664 units (95% CI 0.654-0.671) for FP and 2 health deficits (SD 0.050 [0.048-0.051]) for FI. Agreement of frailty was modest for both measures, but higher for FI (K 0.600 [0.584-0.615]) than FP (K 0.370 [0.348-0.401]). The odds ratios (ORs) for all-cause mortality were higher for frailty assessed using the mean of two versus single measurements for FI (ORs for mortality 3.5 [2.6-4.9] vs. 2.7 [1.9-3.4], respectively) and FP (ORs for mortality 6.9 [4.6-10.3] vs. 4.0 [2.8-5.635], respectively). Frailty scores based on single measurements had substantial within-person variability, but the agreement in classification of frailty was higher for FI than FP. Frailty assessed using the mean of two or more measurements recorded at separate visits was more strongly associated with adverse health outcomes than those recorded at a single visit.

Independent effects of adiposity measures on risk of atrial fibrillation in men and women: a study of 0.5 million individuals.

BACKGROUND: Atrial fibrillation (AF) has a higher prevalence in men than in women and is associated with measures of adiposity and lean mass (LM). However, it remains uncertain whether the risks of AF associated with these measures vary by sex. METHODS: Among 477 904 UK Biobank participants aged 40-69 without prior AF, 23 134 incident AF cases were identified (14 400 men, 8734 women; median follow-up 11.1 years). Cox proportional hazards models were used to estimate the covariate adjusted hazard ratios (HRs) describing the association of AF with weight, measures of adiposity [fat mass (FM), waist circumference (WC)] and LM, and their independent relevance, by sex. RESULTS: Weight and WC were independently associated with risk of AF [HR: 1.25 (1.23-1.27) per 10 kg, HR: 1.11 (1.09-1.14) per 10 cm, respectively], with comparable effects in both sexes. The association with weight was principally driven by LM, which, per 5 kg, conferred double the risk of AF compared with FM when mutually adjusted [HR: 1.20 (1.19-1.21), HR: 1.10 (1.09-1.11), respectively]; however, the effect of LM was weaker in men than in women (p-interaction = 4.3 x 10-9). Comparing the relative effects of LM, FM and WC identified different patterns within each sex; LM was the strongest predictor for both, whereas WC was stronger than FM in men but not in women. CONCLUSIONS: LM and FM (as constituents of weight) and WC are risk factors for AF. However, the independent relevance of general adiposity for AF was more limited in men than in women. The relevance of both WC and LM suggests a potentially important role for visceral adiposity and muscle mass in AF development.

Body-mass index, blood pressure, diabetes and cardiovascular mortality in Cuba: prospective study of 146,556 participants.

BACKGROUND: Cardiovascular disease accounts for about one-third of all premature deaths (ie, age < 70) in Cuba. Yet, the relevance of major risk factors, including systolic blood pressure (SBP), diabetes, and body-mass index (BMI), to cardiovascular mortality in this population remains unclear. METHODS: In 1996-2002, 146,556 adults were recruited from the general population in five areas of Cuba. Participants were interviewed, measured (height, weight and blood pressure) and followed up by electronic linkage to national death registries until Jan 1, 2017; in 2006-08, 24,345 participants were resurveyed. After excluding all with missing data, cardiovascular disease at recruitment, and those who died in the first 5 years, Cox regression (adjusted for age, sex, education, smoking, alcohol and, where appropriate, BMI) was used to relate cardiovascular mortality rate ratios (RRs) at ages 35-79 years to SBP, diabetes and BMI; RR were corrected for regression dilution to give associations with long-term average (ie, 'usual') levels of SBP and BMI. RESULTS: After exclusions, there were 125,939 participants (mean age 53 [SD12]; 55% women). Mean SBP was 124 mmHg (SD15), 5% had diabetes, and mean BMI was 24.2 kg/m2 (SD3.6); mean SBP and diabetes prevalence at recruitment were both strongly related to BMI. During follow-up, there were 4112 cardiovascular deaths (2032 ischaemic heart disease, 832 stroke, and 1248 other). Cardiovascular mortality was positively associated with SBP (>=120 mmHg), diabetes, and BMI (>=22.5 kg/m2): 20 mmHg higher usual SBP about doubled cardiovascular mortality (RR 2.02, 95%CI 1.88-2.18]), as did diabetes (2.15, 1.95-2.37), and 10 kg/m2 higher usual BMI (1.92, 1.64-2.25). RR were similar in men and in women. The association with BMI and cardiovascular mortality was almost completely attenuated following adjustment for the mediating effect of SBP. Elevated SBP (>=120 mmHg), diabetes and raised BMI (>=22.5 kg/m2) accounted for 27%, 14%, and 16% of cardiovascular deaths, respectively. CONCLUSIONS: This large prospective study provides direct evidence for the effects of these major risk factors on cardiovascular mortality in Cuba. Despite comparatively low levels of these risk factors by international standards, the strength of their association with cardiovascular death means they nevertheless exert a substantial impact on premature mortality in Cuba.

Alcohol consumption and cause-specific mortality in Cuba: prospective study of 120 623 adults.

BACKGROUND: The associations of cause-specific mortality with alcohol consumption have been studied mainly in higher-income countries. We relate alcohol consumption to mortality in Cuba. METHODS: In 1996-2002, 146 556 adults were recruited into a prospective study from the general population in five areas of Cuba. Participants were interviewed, measured and followed up by electronic linkage to national death registries until January 1, 2017. After excluding all with missing data or chronic disease at recruitment, Cox regression (adjusted for age, sex, province, education, and smoking) was used to relate mortality rate ratios (RRs) at ages 35-79 years to alcohol consumption. RRs were corrected for long-term variability in alcohol consumption using repeat measures among 20 593 participants resurveyed in 2006-08. FINDINGS: After exclusions, there were 120 623 participants aged 35-79 years (mean age 52 [SD 12]; 67 694 [56%] women). At recruitment, 22 670 (43%) men and 9490 (14%) women were current alcohol drinkers, with 15 433 (29%) men and 3054 (5%) women drinking at least weekly; most alcohol consumption was from rum. All-cause mortality was positively and continuously associated with weekly alcohol consumption: each additional 35cl bottle of rum per week (110g of pure alcohol) was associated with ∼10% higher risk of all-cause mortality (RR 1.08 [95%CI 1.05-1.11]). The major causes of excess mortality in weekly drinkers were cancer, vascular disease, and external causes. Non-drinkers had ∼10% higher risk (RR 1.11 [1.09-1.14]) of all-cause mortality than those in the lowest category of weekly alcohol consumption (<1 bottle/week), but this association was almost completely attenuated on exclusion of early follow-up. INTERPRETATION: In this large prospective study in Cuba, weekly alcohol consumption was continuously related to premature mortality. Reverse causality is likely to account for much of the apparent excess risk among non-drinkers. The findings support limits to alcohol consumption that are lower than present recommendations in Cuba. FUNDING: Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen).

Development and Internal Validation of a Risk Score to Detect Asymptomatic Carotid Stenosis.

OBJECTIVE: Asymptomatic carotid stenosis (ACS) is associated with an increased risk of ischaemic stroke and myocardial infarction. Risk scores have been developed to detect individuals at high risk of ACS, thereby enabling targeted screening, but previous external validation showed scope for refinement of prediction by adding additional predictors. The aim of this study was to develop a novel risk score in a large contemporary screened population. METHODS: A prediction model was developed for moderate (≥50%) and severe (≥70%) ACS using data from 596 469 individuals who attended screening clinics. Variables that predicted the presence of ≥50% and ≥70% ACS independently were determined using multivariable logistic regression. Internal validation was performed using bootstrapping techniques. Discrimination was assessed using area under the receiver operating characteristic curves (AUROCs) and agreement between predicted and observed cases using calibration plots. RESULTS: Predictors of ≥50% and ≥70% ACS were age, sex, current smoking, diabetes mellitus, prior stroke/transient ischaemic attack, coronary artery disease, peripheral arterial disease, blood pressure, and blood lipids. Models discriminated between participants with and without ACS reliably, with an AUROC of 0.78 (95% confidence interval [CI] 0.77-0.78) for ≥ 50% ACS and 0.82 (95% CI 0.81-0.82) for ≥ 70% ACS. The number needed to screen in the highest decile of predicted risk to detect one case with ≥50% ACS was 13 and that of ≥70% ACS was 58. Targeted screening of the highest decile identified 41% of cases with ≥50% ACS and 51% with ≥70% ACS. CONCLUSION: The novel risk model predicted the prevalence of ACS reliably and performed better than previous models. Targeted screening among the highest decile of predicted risk identified around 40% of all cases with ≥50% ACS. Initiation or intensification of cardiovascular risk management in detected cases might help to reduce both carotid related ischaemic strokes and myocardial infarctions.

Validation of Risk Prediction Models to Detect Asymptomatic Carotid Stenosis.

Background Significant asymptomatic carotid stenosis (ACS) is associated with higher risk of strokes. While the prevalence of moderate and severe ACS is low in the general population, prediction models may allow identification of individuals at increased risk, thereby enabling targeted screening. We identified established prediction models for ACS and externally validated them in a large screening population. Methods and Results Prediction models for prevalent cases with ≥50% ACS were identified in a systematic review (975 studies reviewed and 6 prediction models identified [3 for moderate and 3 for severe ACS]) and then validated using data from 596 469 individuals who attended commercial vascular screening clinics in the United States and United Kingdom. We assessed discrimination and calibration. In the validation cohort, 11 178 (1.87%) participants had ≥50% ACS and 2033 (0.34%) had ≥70% ACS. The best model included age, sex, smoking, hypertension, hypercholesterolemia, diabetes mellitus, vascular and cerebrovascular disease, measured blood pressure, and blood lipids. The area under the receiver operating characteristic curve for this model was 0.75 (95% CI, 0.74-0.75) for ≥50% ACS and 0.78 (95% CI, 0.77-0.79) for ≥70% ACS. The prevalence of ≥50% ACS in the highest decile of risk was 6.51%, and 1.42% for ≥70% ACS. Targeted screening of the 10% highest risk identified 35% of cases with ≥50% ACS and 42% of cases with ≥70% ACS. Conclusions Individuals at high risk of significant ACS can be selected reliably using a prediction model. The best-performing prediction models identified over one third of all cases by targeted screening of individuals in the highest decile of risk only.

Impact of public release of performance data on the behaviour of healthcare consumers and providers.

BACKGROUND: It is becoming increasingly common to publish information about the quality and performance of healthcare organisations and individual professionals. However, we do not know how this information is used, or the extent to which such reporting leads to quality improvement by changing the behaviour of healthcare consumers, providers, and purchasers. OBJECTIVES: To estimate the effects of public release of performance data, from any source, on changing the healthcare utilisation behaviour of healthcare consumers, providers (professionals and organisations), and purchasers of care. In addition, we sought to estimate the effects on healthcare provider performance, patient outcomes, and staff morale. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers on 26 June 2017. We checked reference lists of all included studies to identify additional studies. SELECTION CRITERIA: We searched for randomised or non-randomised trials, interrupted time series, and controlled before-after studies of the effects of publicly releasing data regarding any aspect of the performance of healthcare organisations or professionals. Each study had to report at least one main outcome related to selecting or changing care. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for eligibility and extracted data. For each study, we extracted data about the target groups (healthcare consumers, healthcare providers, and healthcare purchasers), performance data, main outcomes (choice of healthcare provider, and improvement by means of changes in care), and other outcomes (awareness, attitude, knowledge of performance data, and costs). Given the substantial degree of clinical and methodological heterogeneity between the studies, we presented the findings for each policy in a structured format, but did not undertake a meta-analysis. MAIN RESULTS: We included 12 studies that analysed data from more than 7570 providers (e.g. professionals and organisations), and a further 3,333,386 clinical encounters (e.g. patient referrals, prescriptions). We included four cluster-randomised trials, one cluster-non-randomised trial, six interrupted time series studies, and one controlled before-after study. Eight studies were undertaken in the USA, and one each in Canada, Korea, China, and The Netherlands. Four studies examined the effect of public release of performance data on consumer healthcare choices, and four on improving quality.There was low-certainty evidence that public release of performance data may make little or no difference to long-term healthcare utilisation by healthcare consumers (3 studies; 18,294 insurance plan beneficiaries), or providers (4 studies; 3,000,000 births, and 67 healthcare providers), or to provider performance (1 study; 82 providers). However, there was also low-certainty evidence to suggest that public release of performance data may slightly improve some patient outcomes (5 studies, 315,092 hospitalisations, and 7502 providers). There was low-certainty evidence from a single study to suggest that public release of performance data may have differential effects on disadvantaged populations. There was no evidence about effects on healthcare utilisation decisions by purchasers, or adverse effects. AUTHORS' CONCLUSIONS: The existing evidence base is inadequate to directly inform policy and practice. Further studies should consider whether public release of performance data can improve patient outcomes, as well as healthcare processes.

Cardiovascular risk factors and frailty in a cross-sectional study of older people: implications for prevention.

Objective: to examine the associations of cardiovascular disease (CVD) and cardiovascular risk factors with frailty. Design: a cross-sectional study. Setting: the Irish Longitudinal Study on Ageing (TILDA). Participants: frailty measures were obtained on 5,618 participants and a subset of 4,330 participants with no prior history of CVD. Exposures for observational study: cardiovascular risk factors were combined in three composite CVD risk scores (Systematic Coronary Risk Evaluation [SCORE], Ideal Cardiovascular Health [ICH] and Cardiovascular Health Metrics [CHM]). Main outcome measures: a frailty index (40-items) was used to screen for frailty. Methods: the associations of CVD risk factors with frailty were examined using logistic regression. Results: overall, 16.4% of participants had frailty (7.6% at 50-59 years to 42.5% at 80+ years), and the prevalence was higher in those with versus those without prior CVD (43.0% vs. 10.7%). Among those without prior CVD, mean levels of CVD risk factors were closely correlated with higher frailty index scores. Combined CVD risk factors, assessed using SCORE, were linearly and positively associated with frailty. Compared to low-to-moderate SCOREs, the odds ratio (OR) (95% confidence interval, CI) of frailty for those with very high risk was 3.18 (2.38-4.25). Conversely, ICH was linearly and inversely associated with frailty, with an OR for optimal health of 0.29 (0.21-0.40) compared with inadequate health. Conclusions: the concordant positive associations of SCORE and inverse associations of ICH and CHM with frailty highlight the potential importance of optimum levels of CVD risk factors for prevention of disability in frail older people.

On the importance of cognitive profiling: A graphical modelling analysis of domain-specific and domain-general deficits after stroke.

Cognitive problems following stroke are typically analysed using either short but relatively uninformative general tests or through detailed but time consuming tests of domain specific deficits (e.g., in language, memory, praxis). Here we present an analysis of neuropsychological deficits detected using a screen designed to fall between other screens by being 'broad' (testing multiple cognitive abilities) but 'shallow' (sampling the abilities briefly, to be time efficient) - the BCoS. Assessment using the Birmingham Cognitive Screen (BCoS) enables the relations between 'domain specific' and 'domain general' cognitive deficits to be evaluated as the test generates an overall cognitive profile for individual patients. We analysed data from 287 patients tested at a sub-acute stage of stroke (<3 months). Graphical modelling techniques were used to investigate the associative structure and conditional independence between deficits within and across the domains sampled by BCoS (attention and executive functions, language, memory, praxis and number processing). The patterns of deficit within each domain conformed to existing cognitive models. However, these within-domain patterns underwent substantial change when the whole dataset was modelled, indicating that domain-specific deficits can only be understood in relation to linked changes in domain-general processes. The data point to the importance of using over-arching cognitive screens, measuring domain-general as well as domain-specific processes, in order to account for neuropsychological deficits after stroke. The paper also highlights the utility of using graphical modelling to understand the relations between cognitive components in complex datasets.

Graphical modeling for gene set analysis: A critical appraisal.

Current demand for understanding the behavior of groups of related genes, combined with the greater availability of data, has led to an increased focus on statistical methods in gene set analysis. In this paper, we aim to perform a critical appraisal of the methodology based on graphical models developed in Massa et al. (2010) that uses pathway signaling networks as a starting point to develop statistically sound procedures for gene set analysis. We pay attention to the potential of the methodology with respect to the organizational aspects of dealing with such complex but highly informative starting structures, that is pathways. We focus on three themes: the translation of a biological pathway into a graph suitable for modeling, the role of shrinkage when more genes than samples are obtained, the evaluation of respondence of the statistical models to the biological expectations. To study the impact of shrinkage, two simulation studies will be run. To evaluate the biological expectation we will use data from a network with known behavior that offer the possibility of carrying out a realistic check of respondence of the model to changes in the experimental conditions.

Along signal paths: an empirical gene set approach exploiting pathway topology.

Gene set analysis using biological pathways has become a widely used statistical approach for gene expression analysis. A biological pathway can be represented through a graph where genes and their interactions are, respectively, nodes and edges of the graph. From a biological point of view only some portions of a pathway are expected to be altered; however, few methods using pathway topology have been proposed and none of them tries to identify the signal paths, within a pathway, mostly involved in the biological problem. Here, we present a novel algorithm for pathway analysis clipper, that tries to fill in this gap. clipper implements a two-step empirical approach based on the exploitation of graph decomposition into a junction tree to reconstruct the most relevant signal path. In the first step clipper selects significant pathways according to statistical tests on the means and the concentration matrices of the graphs derived from pathway topologies. Then, it identifies within these pathways the signal paths having the greatest association with a specific phenotype. We test our approach on simulated and two real expression datasets. Our results demonstrate the efficacy of clipper in the identification of signal transduction paths totally coherent with the biological problem.