Longitudinal analysis of three-dimensional facial shape data

Shape data encompass all the information that is left to describe a shape following removal of location, rotation and scale effects. Much work has been done in the analysis of two-dimensional shapes depicted by anatomical landmarks placed at points of importance. Less has been carried out in the area of three-dimensional shapes, particularly in terms of growth or change over time. This thesis considers the analysis of such longitudinal three-dimensional shape data. In doing so, two well established but normally unrelated areas of Statistics are brought together: those of longitudinal data analysis (specifically, linear mixed effects models) and shape analysis. A recently proposed method of analysing longitudinal high-dimensional data is presented in a novel application within the area of shape analysis, illustrated by a study comparing the facial shapes of cleft-lip and palate children with controls as they grow from three months to two years of age. Both anatomical landmarks and facial curves are considered. Chapter 1 broadly introduces the areas of shape analysis, linear mixed effects models and dimension reduction. Standard methods for measuring shapes are introduced, along with the difficulties inherent in analysing the resulting data. A broad overview of the methods of aligning individual shapes to remove the unwanted effects of location, rotation and scale is given, along with related geometrical issues in terms of the high-dimensional space in which a set of shapes resides. A general introduction to linear mixed effects models compares and contrasts them with simple linear models, explaining the reasons behind using them and presenting the different specifications of the conditional and marginal models. The area of dimension reduction is touched upon, specifically introducing B-splines and principal components analysis, with reference to the analysis of curves consisting of many points at small increments to one another. The data from the cleft-lip and palate study are introduced, along with a discussion of the primary interest of the analysis and the issue of missing data. Chapter 2 presents the statistical definition of a shape and introduces the area of statistical shape analysis in detail, specifically presenting the technicalities of shape space and distances, and methods such as Procrustes alignment of a set of shapes to remove unwanted effects. The concept of tangent coordinates is introduced as a projection of shape data into a Euclidean space, to enable the use of multivariate methods, and an outline given of thin-plate splines and deformations for the analysis of surfaces. Recent literature in the area of shape analysis is presented. Further recent literature addressing the modelling of growth in shapes is presented in Chapter 3, which goes on to discuss the use of linear mixed models on univariate and multivariate longitudinal data. The difficulties of applying mixed models to multivariate data are discussed and a recently proposed alternative method introduced, which involves fitting mixed models to the responses on pairs of outcomes rather than the full set. A description of the R function written as part of this thesis to fit such pairwise models follows, and this is applied to simulated triangles and quadrilaterals as an illustration. The initial application of the pairwise method to the cleft-lip and palate landmark data is presented in Chapter 4. The landmarks are described and the models are fitted to the tangent coordinate responses with different covariance structures for the random effects. The problems that arise and the deficiencies of the fitted models are extensively discussed. Chapter 5 goes on to address the issues raised in Chapter 4. A method of aligning the individual shapes based upon a subset of landmarks is suggested, along with a model that assumes independence of coordinates between dimensions but correlation within, and the benefits of these approaches compared. A simulation study is carried out to investigate the reasons behind and effects of random effects correlations that are estimated as being close to one, concluding that the problem lies in small variances that are poorly estimated, but that this is unlikely to be of severe detriment to the fixed effects estimates. A method of taking the principal components of the tangent coordinates is suggested, where the model responses are the principal components scores, and this proves to be the most appropriate way of applying the pairwise models in terms of model fit and computational efficiency. In Chapter 6, recent literature on the topic of curve analysis is presented, along with the way the facial curves are measured and the need for dimension reduction. Two methods are presented to this end: B-splines and principal components analysis, with the former suffering similar problems to the landmark analyses in terms of poorly estimated random effects variances, and the latter proving more successful. The application of the pairwise models to the principal components scores of the tangent coordinates provides a detailed analysis of the cleft-lip and palate data. Issues surrounding model comparison are addressed in Chapter 7, with several hypothesis tests presented and applied to simulated data. Drawbacks with some of the tests when applied to high dimensional or longitudinal data result in poor performance, but a method suggested by Faraway (1997) and a modification of the likelihood ratio test, both using bootstrapping, show similarly successful results. These are subsequently used to test for any differences in the time trends for the cleft and control groups post-surgery and find that there are significant differences. Condensed forms of this thesis have been presented at invited seminars and international conferences, and may be found in published form in Barry & Bowman (2006), Barry & Bowman (2007) and Barry & Bowman (2008)

Relationship between blood pressure values, depressive symptoms and cardiovascular outcomes in patients with cardiometabolic disease

We studied joint effect of blood pressure-BP and depression on risk of major adverse cardiovascular outcome in patients with existing cardiometabolic disease. A cohort of 35537 patients with coronary heart disease, diabetes or stroke underwent depression screening and BP was recorded concurrently. We used Cox’s proportional hazards to calculate risk of major adverse cardiovascular event-MACE (myocardial infarction/heart failure/stroke or cardiovascular death) over 4 years associated with baseline BP and depression. 11% (3939) had experienced MACE within 4 years. Patients with very high systolic BP-SBP (160-240) hazard ratio-HR 1.28 and with depression (HR 1.22) at baseline had significantly higher adjusted risk. Depression had significant interaction with SBP in risk prediction (p=0.03). Patients with combination of SBP and depression at baseline had 83% higher adjusted risk of MACE, as compared to patients with reference SBP and without depression. Patients with cardiometabolic disease and comorbid depression may benefit from closer monitoring of SBP

Relationship of depression screening in cardiometabolic disease with vascular events and mortality: findings from a large primary care cohort with 4 years follow-up

Aims: Benefits of routine depression screening for cardiometabolic disease patients remain unclear. We examined the association between depression screening and all-cause mortality and vascular events in cardiometabolic disease patients. Methods and results: 125 143 patients with cardiometabolic diseases (coronary heart disease, diabetes or previous stroke) in the UK participated in primary care chronic disease management in 2008/09, which included depression screening using the Hospital Anxiety and Depression Score. 10 670 receiving depression treatment exempted, 35 537 screened, while 78 936 not screened. We studied all-cause mortality and vascular events at 4 years, by electronic data linkage of 124 414 patients (99.4%) on primary care registers to hospital discharge and mortality records and used Cox proportional hazards on matched data using propensity score. Mean age for the screened and not screened population was 69 years (standard deviation—SD 11.9) and 67 years (SD 14.3), respectively; 58% (20 658) of the screened population were men and 65.3% (22 726) were socioeconomically deprived, compared with 54.2% (42 727) and 67.4% (51 686), respectively, in the not screened population. The screened population had lower all-cause mortality (Hazard Ratio—HR 0.89) and vascular events (HR 0.85) in the matched data of N = 21 893 patients each in the screened and the unscreened groups. Conclusion: Depression screening was associated with a reduction in all-cause mortality and vascular events in patients with cardiometabolic diseases. The uptake of screening was poor for unknown reasons. Reverse causality and confounding by disease severity and quality of care are important possible limitations. Further research to determine reproducibility and explore underlying mechanisms is merited

Risk assessment and predicting outcomes in patients with depressive symptoms: a review of potential role of peripheral blood based biomarkers

Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area

General and age-specific fertility rates in non-affective psychosis : population-based analysis of Scottish women

The study was funded by Chief Scientist Office, Scottish Government Health and Social Care Directorate (Grant CZH/4/951), NHS Research Scotland (NHS Research Scotland Career Research Fellowship).Peer reviewedPublisher PD

Associations between significant head injury in male juveniles in prison in Scotland UK and cognitive function, disability and crime: a cross sectional study

Background: Although the prevalence of head injury is estimated to be high in juveniles in prison, the extent of persisting disability is unknown and relationships with offending uncertain. This limited understanding makes it difficult to develop effective management strategies and interventions to improve health or reduce recidivism. This study investigates effects of significant head injury (SHI) on cognitive function, disability and offending in juvenile prisoners, and considers relationships with common comorbidities. Methods: This cross-sectional study recruited male juvenile prisoners in Scotland from Her Majesty’s Young Offenders Institute (HMYOI) Polmont (detaining approximately 305 of 310 male juveniles in prison in Scotland). To be included juveniles had to be 16 years or older, fluent in English, able to participate in assessment, provide informed consent and not have a severe acute disorder of cognition or communication. Head injury, cognition, disability, history of abuse, mental health and problematic substance use were assessed by interview and questionnaire. Results: We recruited 103 (34%) of 305 juvenile males in HMYOI Polmont. The sample was demographically representative of juvenile males in prisons for young offenders in Scotland. SHI was found in 82/103 (80%) and head injury repeated over long periods of time in 69/82 (85%). Disability was associated with SHI in 11/82 (13%) and was significantly associated with mental health problems, particularly anxiety. Group differences on cognitive tests were not found. However the SHI group reported poorer behavioural control on the Dysexecutive Questionnaire and were more often reported for incidents in prison than those without SHI. Characteristics of offending, including violence, did not differ between groups. Conclusions: Although SHI is highly prevalent in juvenile prisoners, associated disability was relatively uncommon. There was no evidence for differences in cognitive test performance or offending in juveniles with and without SHI. However, signs of poorer behavioural control and greater psychological distress in juveniles with SHI suggest that they may be at greater risk of recidivism and of potentially becoming lifelong offenders. This implies a need for remedial programmes for juvenile prisoners to take account of persisting effects of SHI on mental health and self-control and education and to improve their understanding of the effects of SHI reduce the likelihood of cumulative effects from further SHI

A prospective evaluation of the predictive value of faecal calprotectin in quiescent Crohn’s disease

Background: The faecal calprotectin (FC) test is a non-invasive marker for gastrointestinal inflammation. Aim: To determine whether higher FC levels in individuals with quiescent Crohn’s disease are associated with clinical relapse over the ensuing 12 months.<p></p> Methods: A single centre prospective study was undertaken in Crohn's disease patients in clinical remission attending for routine review. The receiver operating characteristic (ROC) curve for the primary endpoint of clinical relapse by 12 months, based on FC at baseline, was calculated. Kaplan-Meier curves of time to relapse were based on the resulting optimal FC cutoff for predicting relapse.<p></p> Results: Of 97 patients recruited, 92 were either followed up for 12 months without relapsing, or reached the primary endpoint within that period. Of these, 10 (11%) had relapsed by 12 months. The median FC was lower for non-relapsers, 96µg/g (IQR 39-237), than for relapsers, 414µg/g (IQR 259-590), (p=0.005). The area under the ROC curve to predict relapse using FC was 77.4%. An optimal cutoff FC value of 240µg/g to predict relapse of quiescent Crohn’s had sensitivity of 80.0% and specificity of 74.4%. Negative predictive value was 96.8% and positive predictive value was 27.6%. FC≥240μg/g was associated with likelihood of relapse 5.7 (95% CI 1.9-17.3) times higher within 2.3 years than lower values (p=0.002).<p></p> Conclusions: In this prospective dataset, FC appears to be a useful, non-invasive tool to help identify quiescent Crohn’s disease patients at a low risk of relapse over the ensuing 12 months. FC of 240µg/g was the optimal cutoff in this cohort.<p></p&gt

Feasibility study of peer-led and school-based social network Intervention (STASH) to promote adolescent sexual health

Background: Effective sex education is the key to good sexual health. Peer-led approaches can augment teacher-delivered sex education, but many fail to capitalise on mechanisms of social influence. We assessed the feasibility of a novel intervention (STASH) in which students (aged 14–16) nominated as influential by their peers were recruited and trained as Peer Supporters (PS). Over a 5–10-week period, they spread positive sexual health messages to friends in their year group, both in-person and via social media, and were supported to do so via weekly trainer-facilitated meetings. The aims of the study were to assess the feasibility of STASH (acceptability, fidelity and reach), to test and refine the programme theory and to establish whether the study met pre-set progression criteria for continuation to larger-scale evaluation. Methods The overall design was a non-randomised feasibility study of the STASH intervention in 6 schools in Scotland. Baseline (n=680) and follow-up questionnaires (approx. 6 months later; n=603) were administered to the intervention year group. The control group (students in year above) completed the follow-up questionnaire only (n=696), 1 year before the intervention group. The PS (n=88) completed a brief web survey about their experience of the role; researchers interviewed participants in key roles (PS (n=20); PS friends (n=22); teachers (n=8); trainers (n=3)) and observed 20 intervention activities. Activity evaluation forms and project monitoring data also contributed information. We performed descriptive quantitative analysis and thematic qualitative analysis. Results: The PS role was acceptable; on average across schools >50% of students nominated as influential by their friends, signed up and were trained (n=104). This equated to 13% of the year group. Trained PS rarely dropped out (97% completion rate) and 85% said they liked the role. Fidelity was good (all bar one trainer-led activity carried out; PS were active). The intervention had good reach; PS were reasonably well connected and perceived as ‘a good mix’ and 58% of students reported exposure to STASH. Hypothesised pre-conditions, contextual influences and mechanisms of change for the intervention were largely confirmed. All bar one of the progression criteria was met. Conclusion: The weight of evidence supports continuation to full-scale evaluation. Trial registration: Current controlled trials ISRCTN97369178

Invasive versus medical management in patients with prior coronary artery bypass surgery with a non-ST segment elevation acute coronary syndrome: a pilot randomized controlled trial

Background: The benefits of routine invasive management in patients with prior coronary artery bypass grafts presenting with non-ST elevation acute coronary syndromes are uncertain because these patients were excluded from pivotal trials. Methods: In a multicenter trial, non-ST elevation acute coronary syndromes patients with prior coronary artery bypass graft were prospectively screened in 4 acute hospitals. Medically stabilized patients were randomized to invasive management (invasive group) or noninvasive management (medical group). The primary outcome was adherence with the randomized strategy by 30 days. A blinded, independent Clinical Event Committee adjudicated predefined composite outcomes for efficacy (all-cause mortality, rehospitalization for refractory ischemia/angina, myocardial infarction, hospitalization because of heart failure) and safety (major bleeding, stroke, procedure-related myocardial infarction, and worsening renal function). Results: Two hundred seventeen patients were screened and 60 (mean±SD age, 71±9 years, 72% male) were randomized (invasive group, n=31; medical group, n=29). One-third (n=10) of the participants in the invasive group initially received percutaneous coronary intervention. In the medical group, 1 participant crossed over to invasive management on day 30 but percutaneous coronary intervention was not performed. During 2-years’ follow-up (median [interquartile range], 744 [570–853] days), the composite outcome for efficacy occurred in 13 (42%) subjects in the invasive group and 13 (45%) subjects in the medical group. The composite safety outcome occurred in 8 (26%) subjects in the invasive group and 9 (31%) subjects in the medical group. An efficacy or safety outcome occurred in 17 (55%) subjects in the invasive group and 16 (55%) subjects in the medical group. Health status (EuroQol 5 Dimensions) and angina class in each group were similar at 12 months. Conclusions: More than half of the population experienced a serious adverse event. An initial noninvasive management strategy is feasible. A substantive health outcomes trial of invasive versus noninvasive management in non-ST elevation acute coronary syndromes patients with prior coronary artery bypass grafts appears warranted. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01895751