Development and validation of risk prediction equations to estimate survival in patients with colorectal cancer: cohort study

Objective: To develop and externally validate risk prediction equations to estimate absolute and conditional survival in patients with colorectal cancer. Design: Cohort study. Setting: General practices in England providing data for the QResearch database linked to the national cancer registry. Participants: 44 145 patients aged 15-99 with colorectal cancer from 947 practices to derive the equations. The equations were validated in 15 214 patients with colorectal cancer from 305 different QResearch practices and 437 821 patients with colorectal cancer from the national cancer registry. Main outcome measures: The primary outcome was all cause mortality and secondary outcome was colorectal cancer mortality. Methods: Cause specific hazards models were used to predict risks of colorectal cancer mortality and other cause mortality accounting for competing risks, and these risk estimates were combined to obtain risks of all cause mortality. Separate equations were derived for men and women. Several variables were tested: age, ethnicity, deprivation score, cancer stage, cancer grade, surgery, chemotherapy, radiotherapy, smoking status, alcohol consumption, body mass index, family history of bowel cancer, anaemia, liver function test result, comorbidities, use of statins, use of aspirin, clinical values for anaemia, and platelet count. Measures of calibration and discrimination were determined in both validation cohorts at 1, 5, and 10 years. Results: The final models included the following variables in men and women: age, deprivation score, cancer stage, cancer grade, smoking status, colorectal surgery, chemotherapy, family history of bowel cancer, raised platelet count, abnormal liver function, cardiovascular disease, diabetes, chronic renal disease, chronic obstructive pulmonary disease, prescribed aspirin at diagnosis, and prescribed statins at diagnosis. Improved survival in women was associated with younger age, earlier stage of cancer, well or moderately differentiated cancer grade, colorectal cancer surgery (adjusted hazard ratio 0.50), family history of bowel cancer (0.62), and prescriptions for statins (0.77) and aspirin (0.83) at diagnosis, with comparable results for men. The risk equations were well calibrated, with predicted risks closely matching observed risks. Discrimination was good in men and women in both validation cohorts. For example, the five year survival equations on the QResearch validation cohort explained 45.3% of the variation in time to colorectal cancer death for women, the D statistic was 1.86, and Harrell’s C statistic was 0.80 (both measures of discrimination, indicating that the scores are able to distinguish between people with different levels of risk). The corresponding results for all cause mortality were 42.6%, 1.77, and 0.79. Conclusions: Risk prediction equations were developed and validated to estimate overall and conditional survival of patients with colorectal cancer accounting for an individual’s clinical and demographic characteristics. These equations can provide more individualised accurate information for patients with colorectal cancer to inform decision making and follow-up

A randomised, controlled trial of a dietary intervention for adults with major depression (the "SMILES" trial): study protocol

Despite increased investment in its recognition and treatment, depression remains a substantial health and economic burden worldwide. Current treatment strategies generally focus on biological and psychological pathways, largely neglecting the role of lifestyle. There is emerging evidence to suggest that diet and nutrition play an important role in the risk, and the genesis, of depression. However, there are limited data regarding the therapeutic impact of dietary changes on existing mental illness. Using a randomised controlled trial design, we aim to investigate the efficacy and cost-efficacy of a dietary program for the treatment of Major Depressive Episodes. <br /

No significant improvement of cardiovascular disease risk indicators by a lifestyle intervention in people with familial hypercholesterolemia compared to usual care: results of a randomised controlled trial

Background: People with Familial Hypercholesterolemia (FH) may benefit from lifestyle changes supporting their primary treatment of dyslipidaemia. This project evaluated the efficacy of an individualised tailored lifestyle intervention on lipids (low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and triglycerides), systolic blood pressure, glucose, body mass index (BMI) and waist circumference in people with FH. Methods: Adults with FH (n= 340), recruited from a Dutch cascade screening program, were randomly assigned to either a control group or an intervention group. The personalised intervention consisted of web-based tailored lifestyle advice and personal counselling. The control group received care as usual. Lipids, systolic blood pressure, glucose, BMI, and waist circumference were measured at baseline and after 12 months. Regression analyses were conducted to examine differences between both groups. Results: After 12 months, no significant between-group differences of cardiovascular disease (CVD) risk indicators were observed. LDL-C levels had decreased in both the intervention and control group. This difference between intervention and control group was not statistically significant. Conclusions: This project suggests that an individually tailored lifestyle intervention did not have an additional effect in improving CVD risk indicators among people with FH. The cumulative effect of many small improvements in all indicators on long term CVD risk remains to be assessed in future studies. Trial registration: NTR1899 at ww.trialregister.nl.© 2012 Broekhuizen et al

Investigating physical health and related secondary care use in people with severe mental illness using electronic health records

Background: People diagnosed with severe mental illness (SMI) have poorer physical health and higher mortality than those without SMI. In this thesis I investigate the physical health and planned and emergency physical health hospital use of people with SMI compared to people without SMI. Methods: I conducted a meta-analysis to quantify excess hospital use for non mental health causes in people with SMI and five physical long-term conditions (LTCs). I used primary care records to investigate the prevalence of 24 LTCs in those with and without SMI, to identify patterns of multimorbidity, and to investigate cancer incidence and mortality. I then linked primary and secondary care records to investigate planned and emergency physical health hospital admissions in people with SMI. Results: Patients with SMI had higher prevalence of 19 of 24 physical LTCs, and of multimorbidity (odds ratio:1.84, 95%CI:1.80-1.88) than those without SMI, with 13 LTCs elevated at or before SMI diagnosis. However, clusters of LTCs were similar between those with and without SMI. Patients with schizophrenia had a lower risk of cancer diagnosis (hazard ratio[HR]:0.83, 95%CI:0.78-0.89) but were at greater risk of cancer mortality (HR:1.93, 95%CI:1.54-2.41) and had fewer planned physical health admissions (incidence rate ratio [IRR]:0.80, 95%CI:0.72- 0.90) than those without SMI. Patients with SMI had more emergency physical health admissions, particularly avoidable admissions (IRR:2.88, 95%CI:2.60- 3.19). Conclusions: Interventions to improve physical health should focus on similar groups of conditions as for the general population, but at a younger age, and early in the course of SMI. The low incidence of cancer and of planned physical health admissions in people with schizophrenia suggest a need for interventions to improve access to preventative and planned services. The high rate of avoidable admissions in those with SMI suggests interventions are required to improve the management of existing physical LTCs

Risk stratification for sudden cardiac death in childhood hypertrophic cardiomyopathy

Sudden cardiac death (SCD) is the most common cause of mortality in childhood onset hypertrophic cardiomyopathy (HCM). Despite this, our understanding of risk factors and ability to identify those at highest risk is limited. The aims of this thesis were to perform the first systematic investigation of SCD in childhood HCM and develop a novel paediatric-specific risk model. Using a large, retrospective, international multi-centre cohort of children with HCM this thesis firstly describes the natural history of childhood onset disease. The second part of the thesis presents the results of the first systematic review and metaanalysis of clinical risk factors for SCD in childhood HCM identifying four major clinical risk factors; previous malignant arrhythmic event, unexplained syncope, nonsustained ventricular tachycardia (NSVT) and extreme left ventricular hypertrophy. In the third part of this thesis, the current risk stratification guidelines are shown to have only moderate discriminatory ability (C statistic 0.62 (95% CI 0.55-0.70)) with a corresponding 5-year positive and negative predictive value of 9.0% and 94.5%. Thus, a novel paediatric model is developed using pre-selected clinical variables from the meta-analysis (unexplained syncope, NSVT, left atrial diameter, maximal wall thickness and left ventricular outflow tract gradient). The model's ability to predict risk at 5 years was validated; C statistic 0.69 (95% CI, 0.66-0.72) and calibration slope 0.98 (95% CI, 0.59-1.38). In the final part of this thesis the role of additional novel risk factors, including 12-lead electrocardiograph and genotype, are explored. In summary, this thesis is the first systematic and comprehensive investigation of risk factors for SCD in childhood HCM. Important differences between adult and childhood disease are described and the first validated risk model for use in paediatric clinical care is presented

Improving early diagnosis of cardiovascular disease in patients with type 2 diabetes and COPD:Protocol of the RED-CVD cluster randomised diagnostic trial

Introduction: The early stages of chronic progressive cardiovascular disease (CVD) generally cause non-specific symptoms that patients often do not spontaneously mention to their general practitioner, and are therefore easily missed. A proactive diagnostic strategy has the potential to uncover these frequently missed early stages, creating an opportunity for earlier intervention. This is of particular importance for chronic progressive CVDs with evidence-based therapies known to improve prognosis, such as ischaemic heart disease, atrial fibrillation and heart failure. Patients with type 2 diabetes or chronic obstructive pulmonary disease (COPD) are at particularly high risk of developing CVD. In the current study, we will demonstrate the feasibility and effectiveness of screening these high-risk patients with our early diagnosis strategy, using tools that are readily available in primary care, such as symptom questionnaires (to be filled out by the patients themselves), natriuretic peptide measurement and electrocardiography. Methods and analysis: The Reviving the Early Diagnosis-CVD trial is a multicentre, cluster randomised diagnostic trial performed in primary care practices across the Netherlands. We aim to include 1300 (2×650) patients who participate in a primary care disease management programme for COPD or type 2 diabetes. Practices will be randomised to the intervention arm (performing the early diagnosis strategy during the routine visits that are part of the disease management programmes) or the control arm (care as usual). The main outcome is the number of newly detected cases with CVDs in both arms, and the subsequent therapies they received. Secondary endpoints include quality of life, cost-effectiveness and the added diagnostic value of family and reproductive history questionnaires and three (novel) biomarkers (high-sensitive troponin-I, growth differentiation factor-15 and suppressor of tumourigenicity 2). Finally newly initiated treatments will be compared in both groups. Ethics and dissemination: The protocol was approved by the Medical Ethical Committee of the University Medical Center Utrecht, the Netherlands. Results are expected in 2022 and will be disseminated through international peer-reviewed publications. Trial registration number NTR7360

Workplace pedometer interventions for increasing physical activity (review)

The World Health Organization recommends that most people should undertake at least 30 minutes of moderate-intensity physical activity on most days, as it reduces the risk of cardiovascular disease, diabetes and some cancers. However, less than 40% of the world’s population are undertaking adequate amounts of physical activity and rates have been declining. Here we assess whether pedometer workplace interventions increase physical activity and thereby lead to subsequent health benefits. To assess this, we searched for randomised controlled trials of workplace health promotion interventions that involved the use of a pedometer undertaken in employed adults. Between 30th January and 6th February 2012 we searched a range of electronic libraries and references of relevant papers, retrieving 3282 potential papers. We eventually included four studies in the review. One study compared pedometer programmes with an alternative physical activity programme, but there were important baseline differences between the intervention and control groups that made it difficult to distinguish the true effect. The three remaining studies compared pedometer programmes with minimally active control groups. One study observed an improvement in physical activity in the pedometer programme, but two other studies found no significant difference between the pedometer group and the control group. We could not combine these results together, as each study used a different measure for physical activity, so it is not clear what the overall effect is. Single studies found beneficial changes in body mass index, fasting plasma glucose, the mental component of quality of life and worksite injury associated with the pedometer programmes as opposed to the control group. However, none of the studies identified consistent differences between the pedometer programme and the control group for waist circumference, blood pressure and quality of life outcomes. In addition, we judged the majority of included studies to have a high risk of bias, mainly due to participants and staff knowing who was in the intervention and who was in the control group, attrition of participants and not having published a protocol prior to running the study. We conclude that there was insufficient evidence to assess whether workplace pedometer interventions are of benefit. There is a need for further high quality randomised controlled trials to be undertaken with a range of health outcomes and assessment in the long term