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Excess body mass index (BMI) is associated with a higher risk of at least 13 cancers, but it is usually measured at a single time point. We tested whether the overweight-years metric, which incorporates exposure time to BMI ≥25 kg/m2 , is associated with cancer risk and compared this with a single BMI measure. We used adulthood BMI readings in the Atherosclerosis Risk in Communities (ARIC) study to derive the overweight-years metric. We calculated associations between the metric and BMI and the risk of cancers using Cox proportional hazards models. Models that either included the metric or BMI were compared using Harrell's C-statistic. We included 13,463 participants, with 3,876 first primary cancers over a mean of 19 years (SD 7) of cancer follow-up. Hazard ratios for obesity-related cancers per standard deviation overweight-years were 1.15 (95% CI: 1.05-1.25) in men and 1.14 (95% CI: 1.08-1.20) in women. The difference in the C-statistic between models that incorporated BMI, or the overweight-years metric was non-significant in men and women. Overweight-years was associated with the risk of obesity-related cancers but did not outperform a single BMI measure in association performance characteristics.
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Aterosclerose , Neoplasias , Masculino , Feminino , Humanos , Adulto , Sobrepeso/complicações , Sobrepeso/epidemiologia , Índice de Massa Corporal , Estudos Prospectivos , Fatores de Risco , Obesidade/complicações , Obesidade/epidemiologia , Neoplasias/etiologia , Neoplasias/complicações , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: In patients with squamous cell carcinoma of the anus (SCCA), magnetic resonance (MR) imaging is recommended for pre-treatment staging prior to chemo-radiotherapy (CRT), but large-scale evaluation of its staging performance is lacking. METHODS: We re-characterised pre-treatment MRs from 228 patients with non-metastatic SCCA treated consecutively by CRT (2006-2015) at one UK cancer centre. We derived TN staging from tumour size (mrTr) and nodal involvement (mrN), and additionally characterised novel beyond TN features such as extramural vascular invasion (mrEMVI) and tumour signal heterogeneity (mrTSH). Primary outcomes were 5-year overall survival (OS) and 3-year loco-regional failure (LRF). Time-to-event analyses used Kaplan-Meier estimates; Hazard Ratios (HRs) with confidence intervals (CIs) were derived from Cox models. RESULTS: With a median follow up of 60.9 months, 5-year OS was 74%. Poor OS was associated with increasing mrT (HR: 1.12 per cm [95% CI: 1.07-1.33]), nodal positivity (HR 2.08 [95% CI 1.23-3.52]) and mrEMVI (HR 3.66 [95% CI: 1.88-7.41]). 3-year LRF rate was 16.5%. Increased LRF was associated with increasing mrT (HR: 1.43 per cm [95% CI: 1.26-1.63]), nodal positivity (HR 2.70 [95% CI 1.39-5.24]) and mrTSH (HR 2.66 [95% CI 1.29-5.48]). CONCLUSIONS: In SCCA, the study demonstrates that mrT and mrN stages are prognostic, while mrEMVI and mrTSH may be novel prognostic factors.
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INTRODUCTION: There is currently no guidance on how to assess the calibration of multistate models used for risk prediction. We introduce several techniques that can be used to produce calibration plots for the transition probabilities of a multistate model, before assessing their performance in the presence of random and independent censoring through a simulation. METHODS: We studied pseudo-values based on the Aalen-Johansen estimator, binary logistic regression with inverse probability of censoring weights (BLR-IPCW), and multinomial logistic regression with inverse probability of censoring weights (MLR-IPCW). The MLR-IPCW approach results in a calibration scatter plot, providing extra insight about the calibration. We simulated data with varying levels of censoring and evaluated the ability of each method to estimate the calibration curve for a set of predicted transition probabilities. We also developed evaluated the calibration of a model predicting the incidence of cardiovascular disease, type 2 diabetes and chronic kidney disease among a cohort of patients derived from linked primary and secondary healthcare records. RESULTS: The pseudo-value, BLR-IPCW, and MLR-IPCW approaches give unbiased estimates of the calibration curves under random censoring. These methods remained predominately unbiased in the presence of independent censoring, even if the censoring mechanism was strongly associated with the outcome, with bias concentrated in low-density regions of predicted transition probability. CONCLUSIONS: We recommend implementing either the pseudo-value or BLR-IPCW approaches to produce a calibration curve, combined with the MLR-IPCW approach to produce a calibration scatter plot. The methods have been incorporated into the "calibmsm" R package available on CRAN.
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Simulação por Computador , Diabetes Mellitus Tipo 2 , Modelos Estatísticos , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Modelos Logísticos , Calibragem , Doenças Cardiovasculares/epidemiologia , Insuficiência Renal Crônica/epidemiologia , ProbabilidadeRESUMO
BACKGROUND: Most cardiac surgery clinical prediction models (CPMs) are developed using pre-operative variables to predict post-operative outcomes. Some CPMs are developed with intra-operative variables, but none are widely used. The objective of this systematic review was to identify CPMs with intra-operative variables that predict short-term outcomes following adult cardiac surgery. METHODS: Ovid MEDLINE and EMBASE databases were searched from inception to December 2022, for studies developing a CPM with at least one intra-operative variable. Data were extracted using a critical appraisal framework and bias assessment tool. Model performance was analysed using discrimination and calibration measures. RESULTS: A total of 24 models were identified. Frequent predicted outcomes were acute kidney injury (9/24 studies) and peri-operative mortality (6/24 studies). Frequent pre-operative variables were age (18/24 studies) and creatinine/eGFR (18/24 studies). Common intra-operative variables were cardiopulmonary bypass time (16/24 studies) and transfusion (13/24 studies). Model discrimination was acceptable for all internally validated models (AUC 0.69-0.91). Calibration was poor (15/24 studies) or unreported (8/24 studies). Most CPMs were at a high or indeterminate risk of bias (23/24 models). The added value of intra-operative variables was assessed in six studies with statistically significantly improved discrimination demonstrated in two. CONCLUSION: Weak reporting and methodological limitations may restrict wider applicability and adoption of existing CPMs that include intra-operative variables. There is some evidence that CPM discrimination is improved with the addition of intra-operative variables. Further work is required to understand the role of intra-operative CPMs in the management of cardiac surgery patients.
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INTRODUCTION: Although lung cancer screening is being implemented in the UK, there is uncertainty about the optimal invitation strategy. Here, we report participation in a community screening programme following a population-based invitation approach, examine factors associated with participation, and compare outcomes with hypothetical targeted invitations. METHODS: Letters were sent to all individuals (age 55-80) registered with a general practice (n=35 practices) in North and East Manchester, inviting ever-smokers to attend a Lung Health Check (LHC). Attendees at higher risk (PLCOm2012NoRace score≥1.5%) were offered two rounds of annual low-dose CT screening. Primary care recorded smoking codes (live and historical) were used to model hypothetical targeted invitation approaches for comparison. RESULTS: Letters were sent to 35 899 individuals, 71% from the most socioeconomically deprived quintile. Estimated response rate in ever-smokers was 49%; a lower response rate was associated with younger age, male sex, and primary care recorded current smoking status (adjOR 0.55 (95% CI 0.52 to 0.58), p<0.001). 83% of eligible respondents attended an LHC (n=8887/10 708). 51% were eligible for screening (n=4540/8887) of whom 98% had a baseline scan (n=4468/4540). Screening adherence was 83% (n=3488/4199) and lung cancer detection 3.2% (n=144) over 2 rounds. Modelled targeted approaches required 32%-48% fewer invitations, identified 94.6%-99.3% individuals eligible for screening, and included 97.1%-98.6% of screen-detected lung cancers. DISCUSSION: Using a population-based invitation strategy, in an area of high socioeconomic deprivation, is effective and may increase screening accessibility. Due to limitations in primary care records, targeted approaches should incorporate historical smoking codes and individuals with absent smoking records.
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Detecção Precoce de Câncer , Neoplasias Pulmonares , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/epidemiologia , Fumantes , Fumar/epidemiologia , Programas de Rastreamento , Fatores SocioeconômicosRESUMO
INTRODUCTION: This study considers the prediction of the time until two survival outcomes have both occurred. We compared a variety of analytical methods motivated by a typical clinical problem of multimorbidity prognosis. METHODS: We considered five methods: product (multiply marginal risks), dual-outcome (directly model the time until both events occur), multistate models (msm), and a range of copula and frailty models. We assessed calibration and discrimination under a variety of simulated data scenarios, varying outcome prevalence, and the amount of residual correlation. The simulation focused on model misspecification and statistical power. Using data from the Clinical Practice Research Datalink, we compared model performance when predicting the risk of cardiovascular disease and type 2 diabetes both occurring. RESULTS: Discrimination was similar for all methods. The product method was poorly calibrated in the presence of residual correlation. The msm and dual-outcome models were the most robust to model misspecification but suffered a drop in performance at small sample sizes due to overfitting, which the copula and frailty model were less susceptible to. The copula and frailty model's performance were highly dependent on the underlying data structure. In the clinical example, the product method was poorly calibrated when adjusting for 8 major cardiovascular risk factors. DISCUSSION: We recommend the dual-outcome method for predicting the risk of two survival outcomes both occurring. It was the most robust to model misspecification, although was also the most prone to overfitting. The clinical example motivates the use of the methods considered in this study.
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Diabetes Mellitus Tipo 2 , Fragilidade , Humanos , Modelos Estatísticos , Simulação por Computador , PrognósticoRESUMO
BACKGROUND: There is growing interest in the collection and use of patient-reported outcome measures (PROMs) to support clinical decision making in patients with non-small cell lung cancer (NSCLC). However, an overview of research into the prognostic value of PROMs is currently lacking. AIM: To explore to what extent, how, and how robustly the value of PROMs for prognostic prediction has been investigated in adults diagnosed with NSCLC. METHODS: We systematically searched Medline, Embase, CINAHL Plus and Scopus for English-language articles published from 2011 to 2021 that report prognostic factor study, prognostic model development or validation study. Example data charting forms from the Cochrane Prognosis Methods Group guided our data charting on study characteristics, PROMs as predictors, predicted outcomes, and statistical methods. Two reviewers independently charted the data and critically appraised studies using the QUality In Prognosis Studies (QUIPS) tool for prognostic factor studies, and the risk of bias assessment section of the Prediction model Risk Of Bias ASsessment Tool (PROBAST) for prognostic model studies. RESULTS: Our search yielded 2,769 unique titles of which we included 31 studies, reporting the results of 33 unique analyses and models. Out of the 17 PROMs used for prediction, the EORTC QLQ-C30 was most frequently used (16/33); 12/33 analyses used PROM subdomain scores instead of the overall scores. PROMs data was mostly collected at baseline (24/33) and predominantly used to predict survival (32/33) but seldom other clinical outcomes (1/33). Almost all prognostic factor studies (26/27) had moderate to high risk of bias and all four prognostic model development studies had high risk of bias. CONCLUSION: There is an emerging body of research into the value of PROMs as a prognostic factor for survival in people with NSCLC but the methodological quality of this research is poor with significant bias. This warrants more robust studies into the prognostic value of PROMs, in particular for predicting outcomes other than survival. This will enable further development of PROM-based prediction models to support clinical decision making in NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Prognóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Viés , Medidas de Resultados Relatados pelo Paciente , Qualidade de VidaRESUMO
AIMS: We evaluated the relationship between body mass index (BMI) and cancer mortality in incident type 2 diabetes. METHODS: We used the Clinical Practice Research Datalink GOLD (1998-2015), linked with the Office of National Statistics mortalities, and derived an incident type 2 diabetes cohort (N = 176 886; aged 30-85 years). We determined BMI ±12 months diabetes diagnosis. The primary outcome was cancer mortality, categorized into deaths from obesity-related cancers (ORCs) and non-ORCs. Secondary outcomes were site-specific cancer mortality and main causes of deaths [cancer, cardiovascular disease (CVD), non-cancer non-CVD]. We developed gender-specific Cox models and expressed risk as hazard ratios and 95% confidence intervals, stratified by smoking status. RESULTS: With 886 850 person-years follow-up, 7593 cancer deaths occurred. Among women who never smoked, there were positive associations between BMI and deaths from endometrial (hazard ratios per 5 kg/m2 : 1.43; 95% confidence interval 1.26-1.61). Among men, associations between BMI and ORC mortality were inverse but attenuated towards null among never smokers and excluding deaths in the first 2 years. In men, the proportion of CVD deaths increased from 36.8% in BMI category 22.5 to 24.9 kg/m2 to 43.6% in BMI category ≥40 kg/m2 (p < .001). CONCLUSIONS: We found some relationships between BMI and cancer mortality in patients with type 2 diabetes, but interpretations need to account for smoking status, reverse causality and deaths from CVD.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Fatores de RiscoRESUMO
Clinical prediction models (CPMs) are often used to guide treatment initiation, with individuals at high risk offered treatment. This implicitly assumes that the probability quoted from a CPM represents the risk to an individual of an adverse outcome in absence of treatment. However, for a CPM to correctly target this estimand requires careful causal thinking. One problem that needs to be overcome is treatment drop-in: where individuals in the development data commence treatment after the time of prediction but before the outcome occurs. In this issue of the Journal, Xu et al. (Am J Epidemiol. 2021;190(10):2000-2014) use causal estimates from external data sources, such as clinical trials, to adjust CPMs for treatment drop-in. This represents a pragmatic and promising approach to address this issue, and it illustrates the value of utilizing causal inference in prediction. Building causality into the prediction pipeline can also bring other benefits. These include the ability to make and compare hypothetical predictions under different interventions, to make CPMs more explainable and transparent, and to improve model generalizability. Enriching CPMs with causal inference therefore has the potential to add considerable value to the role of prediction in healthcare.
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Causalidade , Humanos , ProbabilidadeRESUMO
BACKGROUND: Follicular lymphoma (FL) prognosis is influenced by the composition of the tumour microenvironment. We tested an automated approach to quantitatively assess the phenotypic and spatial immune infiltrate diversity as a prognostic biomarker for FL patients. METHODS: Diagnostic biopsies were collected from 127 FL patients initially treated with rituximab-based therapy (52%), radiotherapy (28%), or active surveillance (20%). Tissue microarrays were constructed and stained using multiplex immunofluorescence (CD4, CD8, FOXP3, CD21, PD-1, CD68, and DAPI). Subsequently, sections underwent automated cell scoring and analysis of spatial interactions, defined as cells co-occurring within 30 µm. Shannon's entropy, a metric describing species biodiversity in ecological habitats, was applied to quantify immune infiltrate diversity of cell types and spatial interactions. Immune infiltrate diversity indices were tested in multivariable Cox regression and Kaplan-Meier analysis for overall (OS) and progression-free survival (PFS). RESULTS: Increased diversity of cell types (HR = 0.19 95% CI 0.06-0.65, p = 0.008) and cell spatial interactions (HR = 0.39, 95% CI 0.20-0.75, p = 0.005) was associated with favourable OS, independent of the Follicular Lymphoma International Prognostic Index. In the rituximab-treated subset, the favourable trend between diversity and PFS did not reach statistical significance. CONCLUSION: Multiplex immunofluorescence and Shannon's entropy can objectively quantify immune infiltrate diversity and generate prognostic information in FL. This automated approach warrants validation in additional FL cohorts, and its applicability as a pre-treatment biomarker to identify high-risk patients should be further explored. The multiplex image dataset generated by this study is shared publicly to encourage further research on the FL microenvironment.
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Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Biomarcadores/metabolismo , Biomarcadores Tumorais/imunologia , Estudos de Coortes , Feminino , Imunofluorescência/métodos , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfoma Folicular/tratamento farmacológico , Masculino , Prognóstico , Intervalo Livre de Progressão , Rituximab/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Clinical prediction models (CPMs) can predict clinically relevant outcomes or events. Typically, prognostic CPMs are derived to predict the risk of a single future outcome. However, there are many medical applications where two or more outcomes are of interest, meaning this should be more widely reflected in CPMs so they can accurately estimate the joint risk of multiple outcomes simultaneously. A potentially naïve approach to multi-outcome risk prediction is to derive a CPM for each outcome separately, then multiply the predicted risks. This approach is only valid if the outcomes are conditionally independent given the covariates, and it fails to exploit the potential relationships between the outcomes. This paper outlines several approaches that could be used to develop CPMs for multiple binary outcomes. We consider four methods, ranging in complexity and conditional independence assumptions: namely, probabilistic classifier chain, multinomial logistic regression, multivariate logistic regression, and a Bayesian probit model. These are compared with methods that rely on conditional independence: separate univariate CPMs and stacked regression. Employing a simulation study and real-world example, we illustrate that CPMs for joint risk prediction of multiple outcomes should only be derived using methods that model the residual correlation between outcomes. In such a situation, our results suggest that probabilistic classification chains, multinomial logistic regression or the Bayesian probit model are all appropriate choices. We call into question the development of CPMs for each outcome in isolation when multiple correlated or structurally related outcomes are of interest and recommend more multivariate approaches to risk prediction.
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Modelos Estatísticos , Teorema de Bayes , Simulação por Computador , Humanos , Modelos Logísticos , PrognósticoRESUMO
BACKGROUND: We tested the hypothesis that body mass index (BMI) aged 20 years modifies the association of adult weight gain and breast cancer risk. METHODS: We recruited women (aged 47-73 years) into the PROCAS (Predicting Risk Of Cancer At Screening; Manchester, UK: 2009-2013) Study. In 47,042 women, we determined BMI at baseline and (by recall) at age 20 years, and derived weight changes. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for new breast cancer using Cox models and explored relationships between BMI aged 20 years, subsequent weight changes and breast cancer risk. RESULTS: With median follow-up of 5.6 years, 1142 breast cancers (post-menopausal at entry: 829) occurred. Among post-menopausal women at entry, BMI aged 20 years was inversely associated [HR per SD: 0.87 (95% CI: 0.79-0.95)], while absolute weight gain was associated with breast cancer [HR per SD:1.23 (95% CI: 1.14-1.32)]. For post-menopausal women who had a recall BMI aged 20 years <23.4 kg/m2 (75th percentile), absolute weight gain was associated with breast cancer [HR per SD: 1.31 (95% CIs: 1.21-1.42)], but there were no associations for women with a recall BMI aged 20 years of >23.4 kg/m2 (Pinteraction values <0.05). CONCLUSIONS: Adult weight gain increased post-menopausal breast cancer risk only among women who were <23.4 kg/m2 aged 20 years.
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Índice de Massa Corporal , Neoplasias da Mama/epidemiologia , Obesidade/epidemiologia , Aumento de Peso/fisiologia , Adulto , Idoso , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/patologia , Pós-Menopausa/fisiologia , Modelos de Riscos Proporcionais , Fatores de Risco , Reino Unido/epidemiologia , Adulto JovemRESUMO
BACKGROUND: We evaluated oncological changes in patients with squamous cell carcinoma of the anus (SCCA) treated by chemoradiotherapy (CRT) from a large UK institute, to derive estimates of contemporary outcomes. METHODS: We performed a treatment-cohort analysis in 560 patients with non-metastatic SCCA treated with CRT over 25 years. The primary outcomes were 3-year loco-regional failure (LRF), 5-year overall survival (OS), and 5-year cancer-specific survival (CSS). We developed prediction models; and overlaid estimates on published results from historic trials. RESULTS: Age distributions, proportions by gender and cT stage remained stable over time. The median follow-up was 61 (IQR: 36-79) months. Comparing the first period (1990-1994) with the last period (2010-2014), 3-year LRF declined from 33 to 16% (Ptrends < 0.001); 5-year OS increased from 60% to 76% (Ptrends = 0.001); and 5-year CCS increased from 62% in to 80% (Ptrends = 0.001). For 2020, the models predicted a 3-year LRF of 14.7% (95% CIs: 0-31.3); 5-year OS of 74.7% (95% CIs: 54.6-94.9); and 5-year CSS of 85.7% (95% CIs: 75.3-96.0). Reported oncological outcomes from historic trials generally underestimated contemporary outcomes. CONCLUSIONS: Current and predicted rates for 3-year LRF and 5-year survivals are considerably improved compared with those in historic trials.
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Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/radioterapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias do Ânus/mortalidade , Carcinoma de Células Escamosas/mortalidade , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Prospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
INTRODUCTION: Exacerbation-prone asthma subtype has been reported in studies using data-driven methodologies. However, patterns of severe exacerbations have not been studied. OBJECTIVE: To investigate longitudinal trajectories of severe wheeze exacerbations from infancy to school age. METHODS: We applied longitudinal k-means clustering to derive exacerbation trajectories among 887 participants from a population-based birth cohort with severe wheeze exacerbations confirmed in healthcare records. We examined early-life risk factors of the derived trajectories, and their asthma-related outcomes and lung function in adolescence. RESULTS: 498/887 children (56%) had physician-confirmed wheeze by age 8 years, of whom 160 had at least one severe exacerbation. A two-cluster model provided the optimal solution for severe exacerbation trajectories among these 160 children: "Infrequent exacerbations (IE)" (n = 150, 93.7%) and "Early-onset frequent exacerbations (FE)" (n = 10, 6.3%). Shorter duration of breastfeeding was the strongest early-life risk factor for FE (weeks, median [IQR]: FE, 0 [0-1.75] vs. IE, 6 [0-20], P < .001). Specific airway resistance (sRaw ) was significantly higher in FE compared with IE trajectory throughout childhood. We then compared children in the two exacerbation trajectories with those who have never wheezed (NW, n = 389) or have wheezed but had no severe exacerbations (WNE, n = 338). At age 8 years, FEV1 /FVC was significantly lower and FeNO significantly higher among FE children compared with all other groups. By adolescence (age 16), subjects in FE trajectory were significantly more likely to have current asthma (67% FE vs. 30% IE vs. 13% WNE, P < .001) and use inhaled corticosteroids (77% FE vs. 15% IE vs. 18% WNE, P < .001). Lung function was significantly diminished in the FE trajectory (FEV1 /FVC, mean [95%CI]: 89.9% [89.3-90.5] vs. 88.1% [87.3-88.8] vs. 85.1% [83.4-86.7] vs. 74.7% [61.5-87.8], NW, WNE, IE, FE respectively, P < .001). CONCLUSION: We have identified two distinct trajectories of severe exacerbations during childhood with different early-life risk factors and asthma-related outcomes in adolescence.
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Asma , Sons Respiratórios , Adolescente , Asma/epidemiologia , Asma/imunologia , Asma/fisiopatologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Testes de Função Respiratória , Fatores de RiscoRESUMO
BACKGROUND: The primary aim was to test the hypothesis that deriving pre-treatment 3D magnetic resonance tumour volume (mrTV) quantification improves performance characteristics for the prediction of loco-regional failure compared with standard maximal tumour diameter (1D) assessment in patients with squamous cell carcinoma of the anus undergoing chemoradiotherapy. METHODS: We performed an early evaluation case-control study at two UK centres (2007-2014) in 39 patients with loco-regional failure (cases), and 41 patients disease-free at 3 years (controls). mrTV was determined using the summation of areas method (Volsum). Reproducibility was assessed using intraclass concordance correlation (ICC) and Bland-Altman limits of agreements. We derived receiver operating curves using logistic regression models and expressed accuracy as area under the curve (ROCAUC). RESULTS: The median time per patient for Volsum quantification was 7.00 (inter-quartile range, IQR: 0.57-12.48) minutes. Intra and inter-observer reproducibilities were generally good (ICCs from 0.79 to 0.89) but with wide limits of agreement (intra-observer: - 28 to 31%; inter-observer: - 28 to 46%). Median mrTVs were greater for cases (32.6 IQR: 21.5-53.1 cm3) than controls (9.9 IQR: 5.7-18.1 cm3, p < 0.0001). The ROCAUC for mrT-size predicting loco-regional failure was 0.74 (95% CI: 0.63-0.85) improving to 0.82 (95% CI: 0.72-0.92) when replaced with mrTV (test for ROC differences, p = 0.024). CONCLUSION: Preliminary results suggest that the replacement of mrTV for mrT-size improves prediction of loco-regional failure after chemoradiotherapy for squamous cell carcinoma of the anus. However, mrTV calculation is time consuming and variation in its reproducibility are drawbacks with the current technology.
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Neoplasias do Ânus/diagnóstico por imagem , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Estudos de Casos e Controles , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Within routinely collected health data, missing data for an individual might provide useful information in itself. This occurs, for example, in the case of electronic health records, where the presence or absence of data is informative. While the naive use of missing indicators to try to exploit such information can introduce bias, its use in conjunction with multiple imputation may unlock the potential value of missingness to reduce bias in causal effect estimation, particularly in missing not at random scenarios and where missingness might be associated with unmeasured confounders. METHODS: We conducted a simulation study to determine when the use of a missing indicator, combined with multiple imputation, would reduce bias for causal effect estimation, under a range of scenarios including unmeasured variables, missing not at random, and missing at random mechanisms. We use directed acyclic graphs and structural models to elucidate a variety of causal structures of interest. We handled missing data using complete case analysis, and multiple imputation with and without missing indicator terms. RESULTS: We find that multiple imputation combined with a missing indicator gives minimal bias for causal effect estimation in most scenarios. In particular the approach: 1) does not introduce bias in missing (completely) at random scenarios; 2) reduces bias in missing not at random scenarios where the missing mechanism depends on the missing variable itself; and 3) may reduce or increase bias when unmeasured confounding is present. CONCLUSION: In the presence of missing data, careful use of missing indicators, combined with multiple imputation, can improve causal effect estimation when missingness is informative, and is not detrimental when missingness is at random.
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Interpretação Estatística de Dados , Viés , Simulação por Computador , HumanosRESUMO
BACKGROUND: Analysis of competing risks is commonly achieved through a cause specific or a subdistribution framework using Cox or Fine & Gray models, respectively. The estimation of treatment effects in observational data is prone to unmeasured confounding which causes bias. There has been limited research into such biases in a competing risks framework. METHODS: We designed simulations to examine bias in the estimated treatment effect under Cox and Fine & Gray models with unmeasured confounding present. We varied the strength of the unmeasured confounding (i.e. the unmeasured variable's effect on the probability of treatment and both outcome events) in different scenarios. RESULTS: In both the Cox and Fine & Gray models, correlation between the unmeasured confounder and the probability of treatment created biases in the same direction (upward/downward) as the effect of the unmeasured confounder on the event-of-interest. The association between correlation and bias is reversed if the unmeasured confounder affects the competing event. These effects are reversed for the bias on the treatment effect of the competing event and are amplified when there are uneven treatment arms. CONCLUSION: The effect of unmeasured confounding on an event-of-interest or a competing event should not be overlooked in observational studies as strong correlations can lead to bias in treatment effect estimates and therefore cause inaccurate results to lead to false conclusions. This is true for cause specific perspective, but moreso for a subdistribution perspective. This can have ramifications if real-world treatment decisions rely on conclusions from these biased results. Graphical visualisation to aid in understanding the systems involved and potential confounders/events leading to sensitivity analyses that assumes unmeasured confounders exists should be performed to assess the robustness of results.
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Modelos Estatísticos , Estudos Observacionais como Assunto/estatística & dados numéricos , Projetos de Pesquisa , Viés , Simulação por Computador , Fatores de Confusão Epidemiológicos , Humanos , Probabilidade , Medição de RiscoRESUMO
PURPOSE: To validate an algorithm for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) episodes derived in an electronic health record (EHR) database, against AECOPD episodes collected in a randomized clinical trial using an electronic case report form (eCRF). METHODS: We analyzed two data sources from the Salford Lung Study in COPD: trial eCRF and the Salford Integrated Record, a linked primary-secondary routine care EHR database of all patients in Salford. For trial participants, AECOPD episodes reported in eCRF were compared with algorithmically derived moderate/severe AECOPD episodes identified in EHR. Episode characteristics (frequency, duration), sensitivity, and positive predictive value (PPV) were calculated. A match between eCRF and EHR episodes was defined as at least 1-day overlap. RESULTS: In the primary effectiveness analysis population (n = 2269), 3791 EHR episodes (mean [SD] length: 15.1 [3.59] days; range: 14-54) and 4403 moderate/severe AECOPD eCRF episodes (mean length: 13.8 [16.20] days; range: 1-372) were identified. eCRF episodes exceeding 28 days were usually broken up into shorter episodes in the EHR. Sensitivity was 63.6% and PPV 71.1%, where concordance was defined as at least 1-day overlap. CONCLUSIONS: The EHR algorithm performance was acceptable, indicating that EHR-derived AECOPD episodes may provide an efficient, valid method of data collection. Comparing EHR-derived AECOPD episodes with those collected by eCRF resulted in slightly fewer episodes, and eCRF episodes of extreme lengths were poorly captured in EHR. Analysis of routinely collected EHR data may be reasonable when relative, rather than absolute, rates of AECOPD are relevant for stakeholders' decision making.
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Registros Eletrônicos de Saúde/estatística & dados numéricos , Farmacoepidemiologia/métodos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Exacerbação dos Sintomas , Idoso , Algoritmos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Coleta de Dados/métodos , Bases de Dados Factuais/estatística & dados numéricos , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Admissão do Paciente/estatística & dados numéricos , Farmacoepidemiologia/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/terapia , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: To measure trends in child growth and combat rising levels of obesity, Manchester University NHS Foundation Trust and the University of Manchester have developed Children's Health and Monitoring Programme (CHAMP). CHAMP collects an annual measurement for primary school children (aged 4 to 11) in Manchester, England, and offers feedback of Body Mass Index (BMI) results to parents via a secure website. No similar digital tool exists that both provides high resolution data on the trajectory of child growth and acts as a feedback and monitoring system. This study investigates how effectively this intervention engaged with parents and supported the reduction of childhood obesity. METHODS: Anonymised CHAMP registration and BMI data (UK1990) were collected between September 2013 and March 2017 from a total of 63,337 children. BMI change over time was compared in matched cohorts of 24,551 children, whose parents had and had not registered with the CHAMP website. Qualitative focus groups and interviews were used to explore perspectives among 29 key informants (parents, school and healthcare professionals) from six schools in Manchester. RESULTS: Overweight children whose parents had not registered with the CHAMP website gained a median of 0.14 BMI centile between measurements, whilst children of CHAMP-registered parents reduced their BMI by a median of 0.4 centile per year (P = 0.02). Normal weight children of registered parents decreased their BMI by 0.3 centile each year, whilst those not registered increased their BMI by 0.8 centile per year (P = 0.001). There was no significant association between registration and BMI centile change in children already classified as obese (P = 0.34). A qualitative, thematic analysis revealed that the annual measurement programme was widely supported by parents and staff. A range of psychological and behavioural impacts on families were reported as a result of the monitoring and feedback processes, in some cases prompting reflection and monitoring of health and lifestyle choices. CONCLUSION: These early findings indicate that CHAMP, as both a monitoring system and a digital intervention, could encourage positive lifestyle change and support healthier child growth trajectories.