EPICure Study Research Articles

Comparing the Prevalence of Psychiatric Disorders in Cohorts of Children Born Extremely Preterm in 1995 and 2006: The EPICure Studies

This study aimed to identify the prevalence of psychiatric disorders in 2 population-based cohorts of children born extremely preterm (EP) 11 years apart to ascertain whether psychiatric outcomes have changed over time following improved survival of EP children. In the EPICure2 study, 200 children born EP (22-26 weeks' gestation) in England in 2006 were assessed at 11 years of age alongside 143 term-born children. Children were assessed using the Developmental and Wellbeing Assessment (DAWBA). DSM-IV diagnoses were assigned by clinical psychiatrists for 145 EP and 98 term-born children. Outcomes were compared between a subsample of children from the EPICure2 cohort (2006, n= 76) and the earlier-born EPICure (1995, n= 161) cohort born at 22 to 25 weeks' gestation in England. EP children in EPICure2 were significantly more likely than term-born children to have any psychiatric disorder (39.3% vs 3.1%; adjusted odds ratio [OR]= 15.1, 95% CI= 4.4-51.1), emotional disorders (14.6% vs 2.0%; OR= 7.3, 95% CI= 1.6-32.7), conduct disorders (6.3% vs 0.0%, p= .01), attention-deficit/hyperactivity disorder (ADHD, 21.9% vs 2.6%; OR= 7.2; 95% CI= 1.5-33.6), and autism spectrum disorder (ASD, 18.9%; vs 0.0%, p< .001). There was no significant difference in the rates of any psychiatric disorder between EP children in the EPICure2 and EPICure cohorts. EP children remain at increased risk for psychiatric disorders at 11 years of age compared with term-born peers. Increased survival has not translated into improved psychiatric outcomes. Health care professionals need to be aware of this ongoing risk when caring for children born preterm.

Effect of digital tools in outpatient cardiac rehabilitation including home training-results of the EPICURE study.

Cardiovascular diseases are the leading cause of death worldwide and are partly caused by modifiable risk factors. Cardiac rehabilitation addresses several of these modifiable risk factors, such as physical inactivity and reduced exercise capacity. However, despite its proven short-term merits, long-term adherence to healthy lifestyle changes is disappointing. With regards to exercise training, it has been shown that rehabilitation supplemented by a) home-based exercise training and b) supportive digital tools can improve adherence. In our multi-center study (ClincalTrials.gov Identifier: NCT04458727), we analyzed the effect of supportive digital tools like digital diaries and/or wearables such as smart watches, activity trackers, etc. on exercise capacity during cardiac rehabilitation. Patients after completion of phase III out-patient cardiac rehabilitation, which included a 3 to 6-months lasting home-training phase, were recruited in five cardiac rehabilitation centers in Austria. Retrospective rehabilitation data were analyzed, and additional data were generated via patient questionnaires. 107 patients who did not use supportive tools and 50 patients using supportive tools were recruited. Already prior to phase III rehabilitation, patients with supportive tools showed higher exercise capacity (Pmax = 186 ± 53 W) as compared to patients without supportive tools (142 ± 41 W, p < 0.001). Both groups improved their Pmax, significantly during phase III rehabilitation, and despite higher baseline Pmax of patients with supportive tools their Pmax improved significantly more (ΔPmax = 19 ± 18 W) than patients without supportive tools (ΔPmax = 9 ± 17 W, p < 0.005). However, after adjusting for baseline differences, the difference in ΔPmax did no longer reach statistical significance. Therefore, our data did not support the hypothesis that the additional use of digital tools like digital diaries and/or wearables during home training leads to further improvement in Pmax during and after phase III cardiac rehabilitation. Further studies with larger sample size, follow-up examinations and a randomized, controlled design are required to assess merits of digital interventions during cardiac rehabilitation.

Comparing behavioural outcomes in children born extremely preterm between 2006 and 1995: the EPICure studies.

Children born extremely preterm (EP) are at increased risk of neurocognitive and behavioural morbidity. Here, we investigate whether behavioural outcomes have changed over time concomitant with increasing survival following EP birth. Comparison of outcomes at 11years of age for two prospective national cohorts of children born EP in 1995 (EPICure) and 2006 (EPICure2), assessed alongside term-born children. Behavioural outcomes were assessed using the parent-completed Strengths and Difficulties Questionnaire (SDQ), DuPaul Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS), and Social Communication Questionnaire (SCQ). In EPICure, 176 EP and 153 term-born children were assessed (mean age: 10.9years); in EPICure2, 112 EP and 143 term-born children were assessed (mean age: 11.8years). In both cohorts, EP children had higher mean scores and more clinically significant difficulties than term-born children on almost all measures. Comparing outcomes for EP children in the two cohorts, there were no significant differences in mean scores or in the proportion of children with clinically significant difficulties after adjustment for confounders. Using term-born children as reference, EP children in EPICure2 had significantly higher SDQ total difficulties and ADHD-RS hyperactivity impulsivity z-scores than EP children in EPICure. Behavioural outcomes have not improved for EP children born in 2006 compared with those born in 1995. Relative to term-born peers, EP children born in 2006 had worse outcomes than those born in 1995. There is an ongoing need for long-term clinical follow-up and psychological support for children born EP.

PERCIST-like response assessment with FDG PET based on automatic segmentation of all lesions in metastatic breast cancer.

e13057 Background: In metastatic breast cancer (MBC), treatment response is often assessed with FDG PET per PERCIST which evaluates changes in SULpeak of the single hottest tumor lesion identified on the baseline and follow-up images. PERCIST therefore does not consider tumor heterogeneity. This work aims to compare responses determined with the automatic segmentation of all lesions to response determined manually per PERCIST. Methods: 10 MBC patients (61±14 y/o) undergoing either chemo- or hormonotherapy were randomly selected from the prospective EPICURE study (NCT03958136). A baseline and two follow-up FDG PET were acquired at pre-, early- (1 month) and mid-treatment times for each patient. All metastatic lesions on all images were manually segmented by experts. Using the Advanced Normalization Tools (ANTs) image registration method, we wrapped baseline lesion segmentations to automatically obtain the follow-up ones. These registered segmentations were compared to the ones done manually using standard biomarkers: SULpeak, lesion size and Total Lesion Glycolysis (TLG). Differences between baseline and follow-up images were visually represented by coloring the follow-up segmentations: in green for responsive lesions (decreasing SULpeak) and in red for progressive ones (increasing SULpeak). Two expert physicians were then asked to evaluate treatment response while seeing these colored segmentations. They assessed the FDG PET images in pairs, evaluating for each patient the baseline and one of the corresponding follow-ups in a blinded manner: either the early- or the mid-treatment follow-up. Evaluations were then compared: i) early- vs mid-treatment response and ii) follow-up response vs patient’s clinical outcome. Results: Biomarkers extracted from the registered segmentations were similar to the ones extracted from the manual segmentations, with a Lin correlation coefficient of 0.92, 0.87 and 0.95 for the SULpeak, lesion size and TLG respectively. These findings were obtained within ̃10min, whereas the manual segmentation of the three PET images for any given patient took ̃1h. With the use of colored segmentations, early follow-up evaluations were predictive of mid-treatment response in 65% of the cases. The blinded physicians agreed with the clinical outcomes 85% and 95% of the time for the early- and mid-treatment images respectively. Conclusions: With segmentations automatically derived from ANTs registration, we managed to extract biomarkers that are comparable to the ones obtained with manual segmentations; both segmentations carried similar information. ANTs fast registration and biomarkers computation can make it a useful tool in clinical routine. In addition, lesion coloring helped evaluate treatment response and early-treatment follow-up images were shown to be predictive of mid-treatment response. Clinical trial information: NCT03958136.

Automatic Segmentation of Metastatic Breast Cancer Lesions on 18F-FDG PET/CT Longitudinal Acquisitions for Treatment Response Assessment.

Simple SummaryIn the recent years, several deep learning methods for medical image segmentation have been developed for different purposes such as diagnosis, radiotherapy planning or to correlate images findings with other clinical data. However, few studies focus on longitudinal images and response assessment. To the best of our knowledge, this is the first study to date evaluating the use of automatic segmentation to obtain imaging biomarkers that can be used to assess treatment response in patients with metastatic breast cancer. Moreover, the statistical analysis of the different biomarkers shows that automatic segmentation can be successfully used for their computation, reaching similar performances compared to manual segmentation. Analysis also demonstrated the potential of the different biomarkers including novel/original ones to determine treatment response.Metastatic breast cancer patients receive lifelong medication and are regularly monitored for disease progression. The aim of this work was to (1) propose networks to segment breast cancer metastatic lesions on longitudinal whole-body PET/CT and (2) extract imaging biomarkers from the segmentations and evaluate their potential to determine treatment response. Baseline and follow-up PET/CT images of 60 patients from the EPICURE study were used to train two deep-learning models to segment breast cancer metastatic lesions: One for baseline images and one for follow-up images. From the automatic segmentations, four imaging biomarkers were computed and evaluated: SUL, Total Lesion Glycolysis (TLG), PET Bone Index (PBI) and PET Liver Index (PLI). The first network obtained a mean Dice score of 0.66 on baseline acquisitions. The second network obtained a mean Dice score of 0.58 on follow-up acquisitions. SUL, with a 32% decrease between baseline and follow-up, was the biomarker best able to assess patients’ response (sensitivity 87%, specificity 87%), followed by TLG (43% decrease, sensitivity 73%, specificity 81%) and PBI (8% decrease, sensitivity 69%, specificity 69%). Our networks constitute promising tools for the automatic segmentation of lesions in patients with metastatic breast cancer allowing treatment response assessment with several biomarkers.

Reduced health-related quality of life in children born extremely preterm in 2006 compared with 1995: the EPICure Studies

ObjectiveTo compare health-related quality of life (HRQL) in childhood for extremely preterm (EP) births before 26 weeks of gestation in England in two eras: 1995 and 2006.DesignProspective cohort studies.SettingSchool or...

Growth in extremely preterm children born in England in 1995 and 2006: the EPICure studies

ObjectivesTo determine growth outcomes at 11 years of age in children born <27 weeks of gestation in England in 2006 (EPICure2) and to compare growth from birth to 11 years...

Extremely preterm birth and autistic traits in young adulthood: the EPICure study

BackgroundA high prevalence of autism spectrum disorder is reported in children born extremely preterm (EP), but an even larger proportion of survivors are affected by subclinical difficulties than meet diagnostic criteria. The aims of this study were to investigate autistic traits associated with the broader autism phenotype in a cohort of young adults born EP, and explore how these traits relate to emotion recognition, empathy and autism symptom presentation in childhood. The prevalence of autism diagnoses was also investigated.MethodsOne hundred and twenty-nine young adults born before 26 weeks of gestation and 65 term-born controls participated in the 19-year follow-up phase of the EPICure studies. In addition to a clinical interview, participants completed the Broader Autism Phenotype Questionnaire (BAPQ), the Empathy Quotient questionnaire, and the Frankfurt Test and Training of Facial Affect Recognition. The Social Communication Questionnaire (SCQ) was completed by the participants’ parents at age 11 years.ResultsEP born young adults scored significantly higher on the BAPQ in comparison with their term-born peers, indicating greater autistic traits. Among EP participants, BAPQ scores were correlated with SCQ scores in childhood (r = 0.484, p < 0.001). EP young adults had significantly lower scores in emotion recognition and empathy in comparison with controls; however, this effect was mediated by IQ. At 19 years, a diagnosis of autism was reported by 10% of EP participants versus 1.6% of controls, whereas 31% of EP participants scored above the cut-off for the broader autism phenotype in comparison with 8.5% of term-born controls.LimitationsThe high attrition of EP participants from lower socio-economic backgrounds and with lower cognitive functioning may have led to an underrepresentation of those presenting with difficulties associated with autism.ConclusionsA larger proportion of EP survivors are affected by difficulties associated with autism than have confirmed diagnoses, with a moderate correlation between autism symptom scores in childhood and autistic traits in young adulthood. EP young adults had significantly higher autism symptom scores and a larger proportion had a diagnosis of autism than controls. Screening for autistic traits at set points throughout childhood will help identify those EP individuals at risk of social difficulties who may benefit from intervention.

Health-Related Quality of Life from Adolescence to Adulthood Following Extremely Preterm Birth

To examine self-reported and parent-reported health-related quality of life (HRQL) in adults born extremely preterm compared with control participants born at term and to evaluate trajectories of health status from adolescence to early adulthood. The EPICure study comprises all births <26weeks of gestation in the United Kingdom and Ireland in 1995 and control participants born at term recruited at age 6years. In total, 129 participants born extremely preterm and 65 control participants were followed up at the 19-year assessment. HRQL was measured by the Health Utilities Index Mark 3 multiattribute utility (MAU) scores. Only parent-reported HRQL was available at 11years of age. Participants born extremely preterm without neurodevelopmental impairment had significantly lower MAU scores at 19years than controls (median [IQR]: 0.91 [0.79, 0.97] vs 0.97 [0.87, 1.00], P=.008); those with impairment had the lowest scores (0.74 [0.49, 0.90]). A 0.03-0.05 difference is considered clinically significant. Parent-reported findings were similar. Participants born extremely preterm with impairment rated their health significantly better than their parents did (0.74 vs 0.58, P=.01), in contrast to those without impairment and controls. Between 11 and 19years, median parent-reported MAU scores decreased from 0.87 to 0.77 for participants born extremely preterm (P=.01) and from 1.00 to 0.97 for control participants (P=.02). Among young adults born extremely preterm, both participants and parents rated their health status less favorably than control participants born at term. The decline in MAU scores from adolescence to early adulthood following extremely preterm birth indicates continuing health issues in young adult life.

The EPICURE study: a pilot prospective cohort study of heterogeneous and massive data integration in metastatic breast cancer patients

BackgroundBreast cancer is the most common cancer in women and the first cancer concerning mortality. Metastatic breast cancer remains a disease with a poor prognosis and about 30% of women diagnosed with an early stage will have a secondary progression. Metastatic breast cancer is an incurable disease despite significant therapeutic advances in both supportive cares and targeted specific therapies. In the management of a metastatic patient, each clinician follows a highly complex and strictly personal decision making process. It is based on a number of objective and subjective parameters which guides therapeutic choice in the most individualized or adapted manner.Methods/designThe main objective is to integrate massive and heterogeneous data concerning the patient’s environment, personal and familial history, clinical and biological data, imaging, histological results (with multi-omics data), and microbiota analysis. These characteristics are multiple and in dynamic interaction overtime. With the help of mathematical units with biological competences and scientific collaborations, our project is to improve the comprehension of treatment response, based on health clinical and molecular heterogeneous big data investigation.DiscussionOur project is to prove feasibility of creation of a clinico-biological database prospectively by collecting epidemiological, socio-economic, clinical, biological, pathological, multi-omic data and to identify characteristics related to the overall survival status before treatment and within 15 years after treatment start from a cohort of 300 patients with a metastatic breast cancer treated in the institution.Trial registrationClinicalTrials.gov identifier (NCT number): NCT03958136. Registration 21st of May, 2019; retrospectively registered.

Size at birth, growth trajectory in early life, and cardiovascular and metabolic risks in early adulthood: EPICure study

ObjectiveTo investigate whether size at birth and growth trajectories in infancy and childhood are associated with determinants of cardiovascular and metabolic risks in young adults born extremely preterm (EP, <26...

The Role of Executive and General Cognitive Functioning in the Attention Problems of Very and Extremely Preterm Adults.

To determine whether the attention problems in adults born very preterm/very low birth weight (VP/VLBW; <32 weeks' gestation/<1500 g) or extremely preterm (EP; <26 weeks' gestation) are associated with specific executive or general cognitive deficits. Cohorts of VP/VLBW (the Bavarian Longitudinal Study [BLS]) and EP (the EPICure Study) participants were followed from birth to early adulthood, each also following a respective control group. Adult attention deficit hyperactivity disorder (ADHD) symptoms were assessed via self-report in both cohorts and additionally by parent report in the BLS. Participants in both cohorts also had their attention span rated by trained observers. Performed separately in each cohort, hierarchical regression analyses were used to assess whether the association between preterm birth status and attention problems remained after accounting for executive functioning (inhibitory control and working memory) in adulthood, childhood intelligence score (IQ), or sex. In the discovery cohort of the BLS, significant differences were found between VP/VLBW adults and controls for parent-rated inattention (p < 0.001). However, for self-reported measures of ADHD, no significant differences were found in the BLS or in the EPICure replication cohort. In both cohorts, observer-rated attention spans were lower for VP/VLBW and EP participants in comparison to their respective control groups (p < 0.001). In final models for the BLS, inhibitory control and childhood IQ were significantly associated with parent-rated inattention symptoms (p < 0.006), whereas working memory and childhood IQ were significantly associated with observer-rated attention span (p < 0.001). The effect of childhood IQ on observer-rated attention span was replicated in EPICure. VP/VLBW and EP adults are at increased risk of observer-rated attention problems. These problems were predominantly associated with poorer general cognitive ability in early childhood and somewhat with adult executive functioning.

Growth to early adulthood following extremely preterm birth: the EPICure study

ObjectiveTo investigate growth trajectories from age 2.5 to 19 years in individuals born before 26 weeks of gestation (extremely preterm; EP) compared with term-born controls.MethodsMultilevel modelling of growth data from...

Testing the neurodevelopmental, trauma and developmental risk factor models of psychosis using a naturalistic experiment.

The neurodevelopmental and trauma theories are two widely cited models of psychosis. A third - the developmental risk factor model (DRFM) - recognises the combined role of neurodevelopmental risks and trauma. Our objective was to test these theories using preterm populations as a natural experiment, given the high prevalence of neurodevelopmental deficits and exposure to trauma. Two population-based preterm birth cohorts, the Bavarian Longitudinal Study (BLS; N = 399) and EPICure Study (N = 184), were included with term-born controls. Peer victimisation in childhood was assessed by parent and child report and psychotic experiences (PE) were assessed in early adulthood. Different models of psychosis were tested using regression and mediation analyses. There was support for the trauma and DRFM in the BLS. Peer victimisation increased the risk of PE for preterm and term-born participants equally [odds ratio = 4.87, 95% confidence interval (CI) 1.96-12.08]. There was an indirect effect where preterm children were more likely to be victimised, which subsequently increased risk of PE [β = 1.12 (s.e. = 0.61), 95% CI 0.11-2.48]. The results were replicated in EPICure. Exposure to trauma which is experienced more often by neurodevelopmental risk children rather than neurodevelopmental risk per se increases the risk of PE. The findings are consistent with the trauma model and DRFM. Interventions focused on reducing trauma may reduce the development of PE.

Hand Preference Develops Across Childhood and Adolescence in Extremely Preterm Children: The EPICure Study

AimWe attempted to determine how handedness changes with age and its relation to brain injury and cognition following birth before 26 weeks of gestation. MethodsWe used data from the EPICure study of health and development following birth in the British Isles in 1995. Handedness was determined by direct observation during standardized testing at age 2.5, six, and 11 years and by self-report using the Edinburgh Handedness Inventory at 19 years. Control data from term births were included at six, 11, and 19 years. ResultsIn extremely preterm children left handedness increased from 9% to 27% between 2.5 and 19 years, with a progressive reduction in mixed handedness from 59% to 13%. Although individual handedness scores varied over childhood, the between-group effects were consistent through 19 years, with greatest differences in females. In extremely preterm participants, neonatal brain injury was associated with lower right handedness scores at each age and left-handed participants had lower cognitive scores at 19 years after controlling for confounders, but not at other ages. ConclusionIncreasing hand lateralization is seen over childhood in extremely preterm survivors, but consistently more individuals have non-right preferences at each age than control individuals.

Airway microbiome in adult survivors of extremely preterm birth: the EPICure study.

Bronchopulmonary dysplasia (BPD) is a major complication of preterm birth that leads to lifelong respiratory morbidity. The EPICure study has investigated the longitudinal health outcomes of infants born extremely preterm (EP; <26 weeks gestation). Our aim was to characterise the airway microbiome in young adults born extremely preterm, with and without neonatal BPD, in comparison to matched term-born controls.Induced sputum was collected from 92 young adults aged 19 years (51 EP and 41 controls). Typical respiratory pathogens were detected using quantitative PCR. 16S rRNA gene sequencing was completed on 74 samples (29 EP with BPD; 9 EP without BPD; and 36 controls).The preterm group with BPD had the least diverse bacterial communities. The relative abundance of Bacteriodetes, particularly Prevotella melaninogenica was significantly lower in the preterm group compared to controls. This decline was balanced by a nonsignificant increase in Firmicutes. Total Prevotella relative abundance correlated with forced expiratory volume in 1 s z-score (ρ=0.272; p<0.05). Typical respiratory pathogen loads and prevalence were similar between groups.In conclusion, extremely preterm birth is associated with a significant dysbiosis in airway microbiome in young adulthood regardless of neonatal BPD status. This is characterised by a shift in the community composition away from Bacteriodetes as manifested in a significant drop in Prevotella relative abundance.

Epidemiology and hospital resources use in the treatment of ulcerative colitis at gastroenterology units in Spain (EPICURE study).

Background and aimNationwide epidemiological data on ulcerative colitis (UC) in Spain are lacking. The primary objective was to assess the epidemiology of UC at hospital gastroenterology units and the use of hospital resources (characteristics and facilities) for the management of UC in Spain.MethodsA retrospective, multicenter, epidemiological, cross-sectional study (EPICURE study) analyzed data from hospital registries and records from UC patients admitted and treated in 2011 at a representative selection of Spanish sites. The prevalence of UC in gastroenterology units was calculated as the total UC patients divided by the total inhabitants covered by those sites. Incidence was defined as the number of new UC cases during 2011 divided by the total inhabitants covered by those sites.ResultsIn 2011, a total of 42,000 patients were attended for UC in gastroenterology units in Spain with a prevalence rate of 88.7 UC cases (95% CI: 69.6–106.0) per 100,000 inhabitants. The incidence rate was of 5.7 cases (95% CI: 1.2–10.8)/100,000 inhabitants. Six percent of patients being attended for UC were hospitalized in the 58 units analyzed in 2011. There were 1075 hospitalizations related to UC in total (approximately 14 per gastroenterology unit; median hospital stay length: 8 days). Six out of 1000 UC patients underwent colectomy in 2011. Near one third (32.7%) were emergency colectomies. Most hospitals had specific IBD units (87.9%) and colorectal surgeons (93.1%).ConclusionsOur study provides the first national data on the prevalence and incidence of UC in gastroenterology units in Spain. Hospitalization and surgical burden associated with UC was low.

Long-term structural and functional visual outcomes in young adults born extremely preterm: the EPICure Study

Long-term structural and functional visual outcomes in young adults born extremely preterm: the EPICure Study

Cardiovascular consequences of extreme prematurity: a follow-up from the EPICure Study

Cardiovascular consequences of extreme prematurity: a follow-up from the EPICure Study

Charting the survival, health and development of extremely preterm infants: EPICure and beyond

Major technological advances and improvements in neonatal medicine in the 1970s and 1980s resulted in significant reductions in mortality rates for babies born at extremely low gestations. In 1992, the gestational age for defining stillbirth in the UK was reduced from 28 weeks to 24 weeks reflecting the marked increase in survival for extremely preterm births. However, as the ‘limits of viability’ were pushed back ever further, there was increasing recognition of the high risk for residual disability amongst extremely preterm survivors. By the mid-1990s, clinicians were aware that the landscape had changed considerably for extremely preterm infants, but wide variation in survival rates between single centres and a lack of standardized developmental follow-up meant that it was difficult to gauge the impact of extremely preterm birth on a national level and to counsel parents as to the likely outcomes for their child. So in 1995, a team of neonatologists in the UK undertook the challenge of carrying out the first national epidemiological study of survival and outcomes following extremely preterm birth, and from that the EPICure Studies were born. Over the last 20 years these and other national cohort studies have helped shape neonatal care and advance our understanding of the life course consequences of extreme prematurity. Here we provide an overview of the key findings from the EPICure Studies and discuss the future challenges faced by clinicians and academics in tackling the causes, consequences and care of extremely preterm births.