Meta-evaluation of a whole systems programme, ActEarly: a study protocol

INTRODUCTION: Living in an area with high levels of child poverty predisposes children to poorer mental and physical health. ActEarly is a 5-year research programme that comprises a large number of interventions (>20) with citizen science and co-production embedded. It aims to improve the health and well-being of children and families living in two areas of the UK with high levels of deprivation; Bradford in West Yorkshire, and the London Borough of Tower Hamlets. This protocol outlines the meta-evaluation (an evaluation of evaluations) of the ActEarly programme from a systems perspective, where individual interventions are viewed as events in the wider policy system across the two geographical areas. It includes investigating the programme's impact on early life health and well-being outcomes, interdisciplinary prevention research collaboration and capacity building, and local and national decision making. METHODS: The ActEarly meta-evaluation will follow and adapt the five iterative stages of the 'Evaluation of Programmes in Complex Adaptive Systems' (ENCOMPASS) framework for evaluation of public health programmes in complex adaptive systems. Theory-based and mixed-methods approaches will be used to investigate the fidelity of the ActEarly research programme, and whether, why and how ActEarly contributes to changes in the policy system, and whether alternative explanations can be ruled out. Ripple effects and systems mapping will be used to explore the relationships between interventions and their outcomes, and the degree to which the ActEarly programme encouraged interdisciplinary and prevention research collaboration as intended. A computer simulation model ("LifeSim") will also be used to evaluate the scale of the potential long-term benefits of cross-sectoral action to tackle the financial, educational and health disadvantages faced by children in Bradford and Tower Hamlets. Together, these approaches will be used to evaluate ActEarly's dynamic programme outputs at different system levels and measure the programme's system changes on early life health and well-being. DISCUSSION: This meta-evaluation protocol presents our plans for using and adapting the ENCOMPASS framework to evaluate the system-wide impact of the early life health and well-being programme, ActEarly. Due to the collaborative and non-linear nature of the work, we reserve the option to change and query some of our evaluation choices based on the feedback we receive from stakeholders to ensure that our evaluation remains relevant and fit for purpose

Meta-evaluation of a whole systems programme, ActEarly: A study protocol

Introduction: Living in an area with high levels of child poverty predisposes children to poorer mental and physical health. ActEarly is a 5-year research programme that comprises a large number of interventions (>20) with citizen science and co-production embedded. It aims to improve the health and well-being of children and families living in two areas of the UK with high levels of deprivation; Bradford in West Yorkshire, and the London Borough of Tower Hamlets. This protocol outlines the meta-evaluation (an evaluation of evaluations) of the ActEarly programme from a systems perspective, where individual interventions are viewed as events in the wider policy system across the two geographical areas. It includes investigating the programme’s impact on early life health and well-being outcomes, interdisciplinary prevention research collaboration and capacity building, and local and national decision making./ Methods: The ActEarly meta-evaluation will follow and adapt the five iterative stages of the ‘Evaluation of Programmes in Complex Adaptive Systems’ (ENCOMPASS) framework for evaluation of public health programmes in complex adaptive systems. Theory-based and mixed-methods approaches will be used to investigate the fidelity of the ActEarly research programme, and whether, why and how ActEarly contributes to changes in the policy system, and whether alternative explanations can be ruled out. Ripple effects and systems mapping will be used to explore the relationships between interventions and their outcomes, and the degree to which the ActEarly programme encouraged interdisciplinary and prevention research collaboration as intended. A computer simulation model (“LifeSim”) will also be used to evaluate the scale of the potential long-term benefits of cross-sectoral action to tackle the financial, educational and health disadvantages faced by children in Bradford and Tower Hamlets. Together, these approaches will be used to evaluate ActEarly’s dynamic programme outputs at different system levels and measure the programme’s system changes on early life health and well-being./ Discussion: This meta-evaluation protocol presents our plans for using and adapting the ENCOMPASS framework to evaluate the system-wide impact of the early life health and well-being programme, ActEarly. Due to the collaborative and non-linear nature of the work, we reserve the option to change and query some of our evaluation choices based on the feedback we receive from stakeholders to ensure that our evaluation remains relevant and fit for purpose

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Wearable activity trackers for young people: usability, acceptability, feasibility, and behaviour change

Background: Physical activity (PA) has numerous immediate and long-term benefits for child and adolescent health and well-being. However, PA levels in children and adolescents are typically low, with few achieving the recommended 60 minutes of moderate-to-vigorous intensity physical activity (MVPA), on average, per day (in 5- to 18-year olds). To date, interventions targeting child and adolescent PA have been limited in their effectiveness. The use of technology (e.g. apps, pedometers) as PA intervention tools have received growing interest, given their increasing availability, affordability and popularity. Previous research has found that wearable activity trackers (wearables) can increase step counts and MVPA in adults, but less is known about their use, acceptability, feasibility, and ability to change behaviour in children and adolescents. Thesis Aims: This thesis aimed to: use theoretical frameworks to investigate what factors impact the habitual use of wearables in children and adolescents (Chapter 2); systematically review the literature investigating the acceptability, feasibility, and effectiveness of wearables for increasing PA, in children and adolescents (Chapter 3); identify behaviour change techniques (BCTs), targeting PA, sedentary time and sleep, embedded within the wearable used in the original studies of this thesis (Fitbit Alta HR; Chapter 4); explore the acceptability of families using wearables (Chapter 5); use behaviour change and co-design approaches to develop a family-based wearable intervention to increase family PA levels (Chapter 6), and outline a protocol for implementing and evaluating the developed intervention (Chapter 7). Methods: Chapter 2: Parents/guardians of 5- to 17-year olds completed a cross-sectional survey, with questions aligned with the theoretical domains framework (TDF) and capability, opportunity, motivation and behaviour (COM-B) model; Chapter 3: Six databases were searched. A narrative review and thematic synthesis were conducted to synthesise the findings, and BCTs in ‘effectiveness’ studies were identified using the BCT taxonomy v1(BCTTv1); Chapter 4: Two authors used the Fitbit Alta HR for four consecutive weeks and used the BCTTv1 to identify BCTs embedded in the Fitbit Alta HR, targeting PA, sedentary time and sleep; Chapter 5: Twenty-five families took part in a five week study where all family members received a Fitbit Alta HR for four weeks. Families’ acceptability of using wearables were explored using questionnaires and focus groups. The technology acceptance model (TAM) and TDF were used as theoretical underpinnings, and quantitative and qualitative data were integrated using the pillar integration process (PIP); Chapter 6: The behaviour change wheel (BCW) and co-design workshops with seven families and seven public health professionals were used to develop a family-based wearable intervention, using composite vignettes that represented barriers to families using wearables to be active (based on previous research; Chapters 3 and 5); Chapter 7: A protocol outlining the implementation and evaluation of the intervention, following recommendations by the Medical Research Council (MRC), was produced.  Results: Chapter 2: Most children and adolescents had never used a wearable (n=429; 51.6%), and 252 (30.3%) and 150 (18.1%) currently or had previously used a wearable, respectively. Reasons for use included interest in technology, and to monitor PA levels, with reasons for disuse or discontinuing use including lack of interest and the cost of wearables. Child and adolescent demographics (age, sex), capability (knowledge of PA), opportunity (parent wearable use), and motivation (enjoyment of PA) were associated with child and adolescent wearable use; Chapter 3: Thirty-three studies were identified. There was some, but mixed, evidence that wearables increased step counts and MVPA, and reduced sedentary time, with no differences based on the number of BCTs incorporated in the intervention. Qualitative accounts suggested wearables increased motivation via self-monitoring, goal setting, feedback, and competition, however, children and adolescents reported technical difficulties and a novelty effect when using wearables; Chapter 4: The Fitbit Alta HR incorporated 25 BCTs, with most BCTs aimed at increasing PA (n=18) and increasing/improving sleep quantity or quality (n=14), with fewer aimed at reducing sedentary time (n=8); Chapter 5: Families’ acceptability of using wearables were synthesised into nine pillars reflecting the six key components of the TAM, and 12 components of the TDF. Families found the Fitbits easy to use and acceptable, but use varied, and perceived impact on PA were mixed, with external variables (e.g. work and school commitments) contributing towards this; Chapter 6: The ‘Move & Connect’ intervention was developed, which is a multi-component flexible intervention targeting family PA and wearable use via education, training, modelling, persuasion, incentivisation and environmental restructuring, and 24 BCTs. Components include Fitbit support resources, PA challenges, reviewing and amending goals and engagement prompts; Chapter 7: The ‘Move & Connect’ intervention is intended to be implemented and evaluated using a pilot randomised controlled trial (RCT) cross-over design, with its acceptability, feasibility, fidelity, and preliminary effectiveness, on family PA levels, co-engagement in PA and physical health, measured.  Conclusions: The work conducted in this thesis represents some of the few studies exploring the use, acceptability, and feasibility of using wearables in children and adolescents. It is the first known series of studies to systematically develop a family-based wearable intervention, targeting PA (‘Move & Connect’), using theoretical underpinnings, previous findings, and co-design approaches. This intervention now warrants implementation and a detailed evaluation to demonstrate its potential feasibility and effectiveness. If shown to be feasible and effective, this intervention could have a positive impact on combating child, and parent, physical inactivity levels.</p