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Background: To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline., Methods: We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor., Results: The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6-69.2%) in 2012 to a median of 72.5% (IQR, 65.3-78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1-69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5-67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2-79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6-76.3%)., Conclusions: The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs., (© 2022. The Author(s).)

Background: The World Health Organization recommends that human growth should be monitored with the use of international standards. However, in obstetric practice, we continue to monitor fetal growth using numerous local charts or equations that are based on different populations for each body structure. Consistent with World Health Organization recommendations, the INTERGROWTH-21 st Project has produced the first set of international standards to date pregnancies; to monitor fetal growth, estimated fetal weight, Doppler measures, and brain structures; to measure uterine growth, maternal nutrition, newborn infant size, and body composition; and to assess the postnatal growth of preterm babies. All these standards are based on the same healthy pregnancy cohort. Recognizing the importance of demonstrating that, postnatally, this cohort still adhered to the World Health Organization prescriptive approach, we followed their growth and development to the key milestone of 2 years of age., Objective: The purpose of this study was to determine whether the babies in the INTERGROWTH-21 st Project maintained optimal growth and development in childhood., Study Design: In the Infant Follow-up Study of the INTERGROWTH-21 st Project, we evaluated postnatal growth, nutrition, morbidity, and motor development up to 2 years of age in the children who contributed data to the construction of the international fetal growth, newborn infant size and body composition at birth, and preterm postnatal growth standards. Clinical care, feeding practices, anthropometric measures, and assessment of morbidity were standardized across study sites and documented at 1 and 2 years of age. Weight, length, and head circumference age- and sex-specific z-scores and percentiles and motor development milestones were estimated with the use of the World Health Organization Child Growth Standards and World Health Organization milestone distributions, respectively. For the preterm infants, corrected age was used. Variance components analysis was used to estimate the percentage variability among individuals within a study site compared with that among study sites., Results: There were 3711 eligible singleton live births; 3042 children (82%) were evaluated at 2 years of age. There were no substantive differences between the included group and the lost-to-follow up group. Infant mortality rate was 3 per 1000; neonatal mortality rate was 1.6 per 1000. At the 2-year visit, the children included in the INTERGROWTH-21 st Fetal Growth Standards were at the 49th percentile for length, 50th percentile for head circumference, and 58th percentile for weight of the World Health Organization Child Growth Standards. Similar results were seen for the preterm subgroup that was included in the INTERGROWTH-21 st Preterm Postnatal Growth Standards. The cohort overlapped between the 3rd and 97th percentiles of the World Health Organization motor development milestones. We estimated that the variance among study sites explains only 5.5% of the total variability in the length of the children between birth and 2 years of age, although the variance among individuals within a study site explains 42.9% (ie, 8 times the amount explained by the variation among sites). An increase of 8.9 cm in adult height over mean parental height is estimated to occur in the cohort from low-middle income countries, provided that children continue to have adequate health, environmental, and nutritional conditions., Conclusion: The cohort enrolled in the INTERGROWTH-21 st standards remained healthy with adequate growth and motor development up to 2 years of age, which supports its appropriateness for the construction of international fetal and preterm postnatal growth standards., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer., Methods: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing., Findings: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12)., Interpretation: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences., Funding: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Early identification of ovarian cancer is an unresolved challenge and the predictive value of single symptoms is limited. We evaluated the performance of QCancer(®) (Ovarian) prediction model for predicting the risk of ovarian cancer in a UK cohort of general practice patients. A total of 1.1 million patients registered with a general practice surgery between 1 January 2000 and 30 June 2008, aged 30-84 years with 735 ovarian cancer cases, were included in the analysis. Ovarian cancer was defined as incident diagnosis of ovarian cancer during the 2 years after study entry. The results from this independent and external validation of QCancer(®) (Ovarian) prediction model demonstrated good performance on a large cohort of general practice patients. QCancer(®) (Ovarian) had very good discrimination with an area under the receiver operating characteristic curve of 0.86 and explained 59.9% of the variation. QCancer(®) (Ovarian) was well calibrated across all tenths of risk and over all age. The 10% of women with the highest predicted risks included 64% of all ovarian cancer diagnoses over the next 2 years. QCancer(®) (Ovarian) appears to be a useful tool for identifying undetected cases of ovarian cancer in primary care in the UK for early referral and investigation., (© 2012 John Wiley & Sons Ltd.)

Introduction: To evaluate the performance of QCancer® (Renal) for predicting the absolute risk of renal tract cancer in a large independent UK cohort of patients from general practice records., Materials and Methods: Open cohort study to validate QCancer® (Renal) prediction model. Record from 365 practices from United Kingdom contributing to The Health Improvement Network (THIN) database. 2.1 million patients registered with a general practice surgery between 01 January 2000 and 30 June 2008, aged 30-84 years (3.7 million person years) with 2283 renal tract cancer cases. Renal tract cancer was defined as incident diagnosis of renal tract cancer during the 2 years after study entry. Model discrimination was measured using the receiver operating characteristics derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities of undetected renal tract cancer., Results: The results from this independent and external validation of QCancer® (Renal) demonstrated good performance data on a large cohort of general practice patients. QCancer® (Renal) had very good discrimination with areas under the ROC curve of 0.92 and 0.95 for women and men respectively. QCancer® (Renal) was well calibrated across all tenths of risk and over all age ranges with predicted risks closely matching observed risks. QCancer® (Renal) explained 74.4% and 74.2% of the variation in men and women respectively. A limitation of our study is the recording of symptoms might be less complete, as patients with mild symptoms may not visit their general practitioner or not report mild symptoms., Conclusions: QCancer® (Renal) are useful tools to help in identifying undetected cases of undiagnosed renal tract cancer in primary care in the UK., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the performance of QCancer® (Gastro-Oesophageal) for predicting the risk of undiagnosed gastro-oesophageal cancer in an independent UK cohort of patients from general practice records., Design: Open cohort study to validate QCancer® (Gastro-Oesophageal) prediction model. Three hundred sixty-five practices from the United Kingdom contributing to The Health Improvement Network database. 2.1 million patients registered with a general practice surgery between 01 January 2000 and 30 June 2008, aged 30-84years (3.7 million person years) with 1766 gastro-oesophageal cancer cases. The outcome, gastro-oesophageal cancer was defined as incident diagnosis of gastro-oesophageal cancer during the 2years after study entry., Results: The results from this independent and external validation of QCancer® (Gastro-Oesophageal) demonstrated good performance data on a large cohort of general practice patients. QCancer® (Gastro-Oesophageal) had very good discrimination with c-statistics of 0.93 and 0.94 for women and men respectively. QCancer® (Gastro-Oesophageal) was well calibrated across all tenths of risk and over all age ranges with predicted risks closely matching observed risks. QCancer® (Gastro-Oesophageal) explained 74.4% and 75.6% of the variation in men and women respectively., Conclusions: QCancer® (Gastro-Oesophageal) is a useful tool to identify undiagnosed gastro-oesophageal cancer in primary care in the United Kingdom., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the performance of the QStatin scores for predicting the 5-year risk of developing acute renal failure, cataract, liver dysfunction and myopathy in men and women in England and Wales receiving statins., Design: Prospective cohort study to evaluate the performance of four statin risk prediction models., Setting: 364 practices in the UK contributing to The Health Improvement Network database., Participants: 2.2 million patients aged 35-84 years registered with a general practice surgery between 1 January 2002 and 30 June 2008, with 2037 incident cases of acute renal failure, 25 692 incident cataract cases, 14 756 cases of liver dysfunction and 1209 incident cases of myopathy., Main Outcome Measures: First recorded occurrence of acute renal failure, cataract, moderate or severe liver dysfunction and moderate or severe myopathic events as recorded in general practice records., Results: Results from this independent and external validation of QStatin scores indicate that models predicting the 5-year statin risk of developing acute renal failure, cataracts and myopathy perform well with areas under the receiver operating characteristic curve ranging from 0.73 to 0.87. Calibration plots for the three models also indicated close agreement between observed and predicted risks. Poor performance was observed for the model predicting the 5-year statin risk of developing liver dysfunction with areas under the receiver operating characteristic curve of 0.64 and 0.60 for women and men, respectively., Conclusions: QStatin scores for predicting the 5-year statin risk of developing acute renal failure, cataract and myopathy appear to be useful models with good discriminative and calibration properties. The model for predicting the 5-year statin risk of developing liver dysfunction appears to have limited ability to identify high-risk individuals and the authors caution against its use.

Objective: To evaluate the performance of the QRISK2-2011 score for predicting the 10 year risk of cardiovascular disease in an independent UK cohort of patients from general practice and to compare it with earlier versions of the model and a National Institute for Health and Clinical Excellence version of the Framingham equation., Design: Prospective cohort study to validate a cardiovascular risk score with routinely collected data between June 1994 and June 2008., Setting: 364 practices from the United Kingdom contributing to The Health Improvement Network (THIN) database., Participants: Two million patients aged 30 to 84 years (11.8 million person years) with 93,564 cardiovascular events., Main Outcome Measure: First diagnosis of cardiovascular disease (myocardial infarction, angina, coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records., Results: Results from this independent and external validation of QRISK2-2011 indicate good performance data when compared with the NICE version of the Framingham equation. QRISK2-2011 had better ability to identify those at high risk of developing cardiovascular disease than did the NICE Framingham equation. QRISK2-2011 is well calibrated, with reasonable agreement between observed and predicted outcomes, whereas the NICE Framingham equation seems to consistently over-predict risk in men by about 5% and shows poor calibration in women., Conclusions: QRISK2-2011 seems to be a useful model, with good discriminative and calibration properties when compared with the NICE version of the Framingham equation. Furthermore, based on current high risk thresholds, concerns exist on the clinical usefulness of the NICE version of the Framingham equation for identifying women at high risk of developing cardiovascular disease. At current thresholds the NICE version of the Framingham equation has no clinical benefit in either men or women.

Objective: To evaluate the performance of the QFractureScores for predicting the 10 year risk of osteoporotic and hip fractures in an independent UK cohort of patients from general practice records., Design: Prospective cohort study., Setting: 364 UK general practices contributing to The Health Improvement Network (THIN) database., Participants: 2.2 million adults registered with a general practice between 27 June 1994 and 30 June 2008, aged 30-85 (13 million person years), with 25,208 osteoporotic fractures and 12,188 hip fractures., Main Outcome Measures: First (incident) diagnosis of osteoporotic fracture (vertebra, distal radius, or hip) and incident hip fracture recorded in general practice records., Results: Results from this independent and external validation of QFractureScores indicated good performance data for both osteoporotic and hip fracture end points. Discrimination and calibration statistics were comparable to those reported in the internal validation of QFractureScores. The hip fracture score had better performance data for both women and men. It explained 63% of the variation in women and 60% of the variation in men, with areas under the receiver operating characteristic curve of 0.89 and 0.86, respectively. The risk score for osteoporotic fracture explained 49% of the variation in women and 38% of the variation in men, with corresponding areas under the receiver operating characteristic curve of 0.82 and 0.74. QFractureScores were well calibrated, with predicted risks closely matching those across all 10ths of risk and for all age groups., Conclusion: QFractureScores are useful tools for predicting the 10 year risk of osteoporotic and hip fractures in patients in the United Kingdom.

Objective: To evaluate the performance of the QRISK2 score for predicting 10-year cardiovascular disease in an independent UK cohort of patients from general practice records and to compare it with the NICE version of the Framingham equation and QRISK1., Design: Prospective cohort study to validate a cardiovascular risk score., Setting: 365 practices from United Kingdom contributing to The Health Improvement Network (THIN) database., Participants: 1.58 million patients registered with a general practice between 1 January 1993 and 20 June 2008, aged 35-74 years (9.4 million person years) with 71 465 cardiovascular events., Main Outcome Measures: First diagnosis of cardiovascular disease (myocardial infarction, angina, coronary heart disease, stroke, and transient ischaemic stroke) recorded in general practice records., Results: QRISK2 offered improved prediction of a patient's 10-year risk of cardiovascular disease over the NICE version of the Framingham equation. Discrimination and calibration statistics were better with QRISK2. QRISK2 explained 33% of the variation in men and 40% for women, compared with 29% and 34% respectively for the NICE Framingham and 32% and 38% respectively for QRISK1. The incidence rate of cardiovascular events (per 1000 person years) among men in the high risk group was 27.8 (95% CI 27.4 to 28.2) with QRISK2, 21.9 (21.6 to 22.2) with NICE Framingham, and 24.8 (22.8 to 26.9) with QRISK1. Similarly, the incidence rate of cardiovascular events (per 1000 person years) among women in the high risk group was 24.3 (23.8 to 24.9) with QRISK2, 20.6 (20.1 to 21.0) with NICE Framingham, and 21.8 (18.9 to 24.6) with QRISK1., Conclusions: QRISK2 is more accurate in identifying a high risk population for cardiovascular disease in the United Kingdom than the NICE version of the Framingham equation. Differences in performance between QRISK2 and QRISK1 were marginal.

Publication bias has been previously identified as a threat to the validity of a meta-analysis. Recently, new evidence has documented an additional threat to validity, the selective reporting of trial outcomes within published studies. Several diseases have several possible measures of outcome. Some articles might report only a selection of those outcomes, perhaps those with statistically significant results. In this article, we review this problem while addressing the questions: what is within-study selective reporting? how common is it? why is it done? how can it mislead? how can it be detected?, and finally, what is the solution? We recommend that both publication bias and selective reporting should be routinely investigated in systematic reviews.