Ethnic disparities in quality of diabetes care in Scotland: A national cohort study.

AIMS: The aim of this study is to compare quality of diabetes care in people with type 2 diabetes by ethnicity, in Scotland. METHODS: Using a linked national diabetes registry, we included 162,122 people newly diagnosed with type 2 diabetes between 2009 and 2018. We compared receipt of nine guideline indicated processes of care in the first-year post-diabetes diagnosis using logistic regression, comparing eight ethnicity groups to the White group. We compared annual receipt of HbA1c and eye screening during the entire follow-up using generalised linear mixed effects. All analyses adjusted for confounders. RESULTS: Receipt of diabetes care was lower in other ethnic groups compared to White people in the first-year post-diagnosis. Differences were most pronounced for people in the: African, Caribbean or Black; Indian; and other ethnicity groups for almost all processes of care. For example, compared to White people, odds of HbA1c monitoring were: 44% lower in African, Caribbean or Black people (OR 0.56 [95% CI 0.48, 0.66]); 47% lower in Indian people (OR 0.53 [95% CI 0.47, 0.61]); and 50% lower in people in the other ethnicity group (OR 0.50 [95% CI 0.46, 0.58]). Odds of receipt of eye screening were 30%-40% lower in most ethnic groups compared to the White group. During median 5 year follow-up, differences in HbA1c monitoring and eye screening largely persisted, but attenuated slightly for the former. CONCLUSIONS: There are marked ethnic disparities in routine diabetes care in Scotland in the short- and medium-term following diabetes diagnosis. Further investigation is needed to establish and effectively address the underlying reasons.

Trends in cause-specific mortality among people with type 2 and type 1 diabetes from 2002 to 2019: a Danish population-based study.

Background: Despite advances in primary and secondary prevention of cardiovascular disease, excess mortality persists within the diabetes population. This study explores the components of this excess mortality and their interaction with sex. Methods: Using Danish registries (2002-2019), we identified residents aged 18-99 years, their diabetes status, and recorded causes of death. Applying Lexis-based methods, we computed age-standardized mortality rates (asMRs), mortality relative risks (asMRRs), and log-linear trends for cause-specific mortality. Findings: From 2002 to 2019, 958,278 individuals died in Denmark (T2D: 148,620; T1D: 7830) during 84.4 M person-years. During the study period, overall asMRs declined, driven by reducing cardiovascular mortality, notably in men with T2D. Conversely, cancer mortality remained high, making cancer the leading cause of death in individuals with T2D. Individuals with T2D faced an elevated mortality risk from nearly all cancer types, ranging from 9% to 257% compared to their non-diabetic counterparts. Notably, obesity-related cancers exhibited the highest relative risks: liver cancer (Men: asMRR 3.58 (3.28; 3.91); Women: asMRR 2.49 (2.14; 2.89)), pancreatic cancer (Men: asMRR 3.50 (3.25; 3.77); Women: asMRR 3.57 (3.31; 3.85)), and kidney cancer (Men: asMRR 2.10 (1.84; 2.40); Women: asMRR 2.31 (1.92; 2.79)). In men with type 2 diabetes, excess mortality remained stable, except for dementia. In women, diabetes-related excess mortality increased by 6-17% per decade across all causes of death, except cardiovascular disease. Interpretation: In the last decade, cancer has emerged as the leading cause of death among individuals with T2D in Denmark, emphasizing the need for diabetes management strategies incorporating cancer prevention. A sex-specific approach is crucial to address persistently higher relative mortality in women with diabetes. Funding: Supported by Steno Diabetes Center Aarhus, which is partially funded by an unrestricted donation from the Novo Nordisk Foundation, and by The Danish Diabetes Academy.

Participant characteristics and exclusion from phase 3/4 industry funded trials of chronic medical conditions: meta-analysis of individual participant level data.

Objectives: To assess whether age, sex, comorbidity count, and race and ethnic group are associated with the likelihood of trial participants not being enrolled in a trial for any reason (ie, screen failure). Design: Bayesian meta-analysis of individual participant level data. Setting: Industry funded phase 3/4 trials of chronic medical conditions. Participants: Participants were identified using individual participant level data to be in either the enrolled group or screen failure group. Data were available for 52 trials involving 72 178 screened individuals of whom 24 733 (34%) were excluded from the trial at the screening stage. Main outcome measures: For each trial, logistic regression models were constructed to assess likelihood of screen failure in people who had been invited to screening, and were regressed on age (per 10 year increment), sex (male v female), comorbidity count (per one additional comorbidity), and race or ethnic group. Trial level analyses were combined in Bayesian hierarchical models with pooling across condition. Results: In age and sex adjusted models across all trials, neither age nor sex was associated with increased odds of screen failure, although weak associations were detected after additionally adjusting for comorbidity (odds ratio of age, per 10 year increment was 1.02 (95% credibility interval 1.01 to 1.04) and male sex (0.95 (0.91 to 1.00)). Comorbidity count was weakly associated with screen failure, but in an unexpected direction (0.97 per additional comorbidity (0.94 to 1.00), adjusted for age and sex). People who self-reported as black seemed to be slightly more likely to fail screening than people reporting as white (1.04 (0.99 to 1.09)); a weak effect that seemed to persist after adjustment for age, sex, and comorbidity count (1.05 (0.98 to 1.12)). The between-trial heterogeneity was generally low, evidence of heterogeneity by sex was noted across conditions (variation in odds ratios on log scale of 0.01-0.13). Conclusions: Although the conclusions are limited by uncertainty about the completeness or accuracy of data collection among participants who were not randomised, we identified mostly weak associations with an increased likelihood of screen failure for age, sex, comorbidity count, and black race or ethnic group. Proportionate increases in screening these underserved populations may improve representation in trials. Trial registration number: PROSPERO CRD42018048202.

Trends in Incidence of Hospitalization for Hypoglycemia and Diabetic Ketoacidosis in Individuals With Type 1 or Type 2 Diabetes With and Without Severe Mental Illness in Denmark From 1996 to 2020: A Nationwide Study.

OBJECTIVE: To examine trends in incidence of acute diabetes complications in individuals with type 1 or type 2 diabetes with and without severe mental illness (SMI) in Denmark by age and calendar year. RESEARCH DESIGN AND METHODS: We conducted a cohort study using nationwide registers from 1996 to 2020 to identify individuals with diabetes, ascertain SMI status (namely, schizophrenia, bipolar disorder, or major depression) and identify the outcomes: hospitalization for hypoglycemia and diabetic ketoacidosis (DKA). We used Poisson regression to estimate incidence rates (IRs) and incidence rate ratios (IRRs) of recurrent hypoglycemia and DKA events by SMI, age, and calendar year, accounting for sex, diabetes duration, education, and country of origin. RESULTS: Among 433,609 individuals with diabetes, 8% had SMI. Risk of (first and subsequent) hypoglycemia events was higher for individuals with SMI than for those without SMI (for first hypoglycemia event, IRR: type 1 diabetes, 1.77 [95% CI 1.56-2.00]; type 2 diabetes, 1.64 [95% CI 1.55-1.74]). Individuals with schizophrenia were particularly at risk for recurrent hypoglycemia events. The risk of first DKA event was higher in individuals with SMI (for first DKA event, IRR: type 1 diabetes, 1.78 [95% CI 1.50-2.11]; type 2 diabetes, 1.85 [95% CI 1.64-2.09]). Except for DKA in the type 2 diabetes group, IR differences between individuals with and without SMI were highest in younger individuals (<50 years old) but stable across the calendar year. CONCLUSIONS: SMI is an important risk factor for acute diabetes complication and effective prevention is needed in this population, especially among the younger population and those with schizophrenia.

Variation in colorectal cancer treatment and outcomes in Scotland: real world evidence from national linked administrative health data.

Background: Colorectal cancer (CRC) is the fourth most common type of cancer in the United Kingdom and the second leading cause of cancer death. Despite improvements in CRC survival over time, Scotland lags behind its UK and European counterparts. In this study, we carry out an exploratory analysis which aims to provide contemporary, population level evidence on CRC treatment and survival in Scotland. Methods: We conducted a retrospective population-based analysis of adults with incident CRC registered on the Scottish Cancer Registry (Scottish Morbidity Record 06 (SMR06)) between January 2006 and December 2018. The CRC cohort was linked to hospital inpatient (SMR01) and National Records of Scotland (NRS) deaths records allowing a description of their demographic, diagnostic and treatment characteristics. Cox proportional hazards regression models were used to explore the demographic and clinical factors associated with all-cause mortality and CRC specific mortality after adjusting for patient and tumour characteristics among people identified as early-stage and treated with surgery. Results: Overall, 32,691 (73%) and 12,184 (27%) patients had a diagnosis of colon and rectal cancer respectively, of whom 55% and 53% were early-stage and treated with surgery. Five year overall survival (CRC specific survival) within this cohort was 72% (82%) and 76% (84%) for patients with colon and rectal cancer respectively. Cox proportional hazards models revealed significant variation in mortality by sex, area-based deprivation and geographic location. Conclusions: In a Scottish population of patients with early-stage CRC treated with surgery, there was significant variation in risk of death, even after accounting for clinical factors and patient characteristics.

Baseline and change in serum uric acid level over time and resolution of nonalcoholic fatty liver disease in young adults: The Kangbuk Samsung Health Study.

AIMS: To determine the association between: (i) baseline serum uric acid (SUA) level and (ii) SUA changes over time, and nonalcoholic fatty liver disease (NAFLD) resolution. MATERIALS AND METHODS: A retrospective cohort study, comprising 38 483 subjects aged <40 years with pre-existing NAFLD, was undertaken. The effects of SUA changes over time were studied in 25 266 subjects. Participants underwent a health examination between 2011 and 2019, and at least one follow-up liver ultrasonography scan up to December 2020. Exposures included baseline SUA level and SUA changes between baseline and subsequent visits, categorized into quintiles. The reference group was the third quintile (Q3) containing zero change. The primary endpoint was resolution of NAFLD. RESULTS: During a median follow-up of 4 years, low baseline SUA level and decreases in SUA levels over time were independently associated with NAFLD resolution (p for trend <0.001). Using SUA as a continuous variable, the likelihood of NAFLD resolution was increased by 10% and 13% in men and women, respectively, per 1-mg/dL decrease in SUA. In a time-dependent model with changes in SUA treated as a time-varying covariate, adjusted hazard ratios (95% confidence intervals) for NAFLD resolution comparing Q1 (highest decrease) and Q2 (slight decrease) to Q3 (reference) were 1.63 (1.49-1.78) and 1.23 (1.11-1.35) in men and 1.78 (1.49-2.12) and 1.18 (0.95-1.46) in women, respectively. CONCLUSIONS: Low baseline SUA levels and a decrease in SUA levels over time were both associated with NAFLD resolution in young adults.

Cardiovascular risk management among individuals with type 2 diabetes and severe mental illness: a cohort study.

AIMS/HYPOTHESIS: The aim of this study was to compare cardiovascular risk management among people with type 2 diabetes according to severe mental illness (SMI) status. METHODS: We used linked electronic data to perform a retrospective cohort study of adults diagnosed with type 2 diabetes in Scotland between 2004 and 2020, ascertaining their history of SMI from hospital admission records. We compared total cholesterol, systolic BP and HbA1c target level achievement 1 year after diabetes diagnosis, and receipt of a statin prescription at diagnosis and 1 year thereafter, by SMI status using logistic regression, adjusting for sociodemographic factors and clinical history. RESULTS: We included 291,644 individuals with type 2 diabetes, of whom 1.0% had schizophrenia, 0.5% had bipolar disorder and 3.3% had major depression. People with SMI were less likely to achieve cholesterol targets, although this difference did not reach statistical significance for all disorders. However, people with SMI were more likely to achieve systolic BP targets compared to those without SMI, with effect estimates being largest for schizophrenia (men: adjusted OR 1.72; 95% CI 1.49, 1.98; women: OR 1.64; 95% CI 1.38, 1.96). HbA1c target achievement differed by SMI disorder and sex. Among people without previous CVD, statin prescribing was similar or better in those with vs those without SMI at diabetes diagnosis and 1 year later. In people with prior CVD, SMI was associated with lower odds of statin prescribing at diabetes diagnosis (schizophrenia: OR 0.54; 95% CI 0.43, 0.68, bipolar disorder: OR 0.75; 95% CI 0.56, 1.01, major depression: OR 0.92; 95% CI 0.83, 1.01), with this difference generally persisting 1 year later. CONCLUSIONS/INTERPRETATION: We found disparities in cholesterol target achievement and statin prescribing by SMI status. This reinforces the importance of clinical review of statin prescribing for secondary prevention of CVD, particularly among people with SMI.

The future of International Classification of Diseases coding in steatotic liver disease: An expert panel Delphi consensus statement.

BACKGROUND: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. METHODS: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. RESULTS: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). CONCLUSIONS: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Severe depression and all-cause and cause-specific mortality in Scotland: 20 year national cohort study.

BACKGROUND: Understanding cause of death in people with depression could inform approaches to reducing premature mortality. AIM: To describe all-cause and cause-specific mortality for people with severe depression in Scotland, by sex, relative to the general population. METHOD: We performed a retrospective cohort study, using psychiatric hospital admission data linked to death data, to identify adults (≥18 years old) with severe depression and ascertain cause-specific deaths, during 2000-2019. We estimated relative all-cause and cause-specific mortality for people with severe depression using standardised mortality ratios (SMRs), stratified by sex using the whole Scottish population as the standard. RESULTS: Of 28 808 people with severe depression, 7903 (27.4%) died during a median follow-up of 8.7 years. All-cause relative mortality was over three times higher than expected (SMR, both sexes combined: 3.26, 95% CI 3.19-3.34). Circulatory disease was the leading cause of death, and, among natural causes of death, excess relative mortality was highest for circulatory diseases (SMR 2.51, 2.40-2.66), respiratory diseases (SMR 3.79, 3.56-4.01) and 'other' causes (SMR 4.10, 3.89-4.30). Among circulatory disease subtypes, excess death was highest for cerebrovascular disease. Both males and females with severe depression had higher all-cause and cause-specific mortality than the general population. Suicide had the highest SMR among both males (SMR 12.44, 95% CI 11.33-13.54) and females (22.86, 95% CI 20.35-25.36). CONCLUSION: People with severe depression have markedly higher all-cause mortality than the general population in Scotland, with relative mortality varying by cause of death. Effective interventions are needed to reduce premature mortality for people with severe depression.

Potential role of Fibrosis-4 score in hepatocellular carcinoma screening: The Kangbuk Samsung Health Study.

AIM: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death, with low survival rates worldwide. Fatty liver disease (FLD) significantly contributes to HCC. We studied the screening performance of different methods for identifying HCC in patients with FLD or with metabolic risk factors for FLD. METHODS: Korean adults (n = 340 825) without a prior HCC diagnosis were categorized into four groups: normal (G1), ≥2 metabolic risk factors (G2), FLD (G3), and viral liver disease or liver cirrhosis (G4). The National Cancer Registry data were used to identify HCC cases within 12 months. We assessed the area under the receiver operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of individual or combined screening methods. RESULTS: In 93 HCC cases, 71 were identified in G4, whereas 20 cases (21.5%) in G2 and G3 combined where ultrasound and Fibrosis-4 performed similarly to alpha-fetoprotein and ultrasound. In G2, Fibrosis-4 and ultrasound had the highest area under the receiver operating characteristic curve (0.93 [0.87-0.99]), whereas in G3, the combined screening methods had the highest area under the receiver operating characteristic curve (0.98 [0.95-1.00]). The positive predictive value was lower in G2 and G3 than in G4, but was >5% when restricted to a high Fibrosis-4 score. CONCLUSIONS: More than 21% of HCC cases were observed in patients with diagnosed FLD or at risk of FLD with metabolic risk factors. Nevertheless, screening for HCC in individuals without cirrhosis or viral hepatitis yielded very low results, despite the potential value of the Fibrosis-4 score in identifying individuals at high risk of HCC.

Correlations between comorbidities in trials and the community: An individual-level participant data meta-analysis.

Background: People with comorbidities are under-represented in randomised controlled trials, and it is unknown whether patterns of comorbidity are similar in trials and the community. Methods: Individual-level participant data were obtained for 83 clinical trials (54,688 participants) for 16 index conditions from two trial repositories: Yale University Open Data Access (YODA) and the Centre for Global Clinical Research Data (Vivli). Community data (860,177 individuals) were extracted from the Secure Anonymised Information Linkage (SAIL) databank for the same index conditions. Comorbidities were defined using concomitant medications. For each index condition, we estimated correlations between comorbidities separately in trials and community data. For the six commonest comorbidities we estimated all pairwise correlations using Bayesian multivariate probit models, conditioning on age and sex. Correlation estimates from trials with the same index condition were combined into a single estimate. We then compared the trial and community estimates for each index condition. Results: Despite a higher prevalence of comorbidities in the community than in trials, the correlations between comorbidities were mostly similar in both settings. On comparing correlations between the community and trials, 21% of correlations were stronger in the community, 10% were stronger in the trials and 68% were similar in both. In the community, 5% of correlations were negative, 21% were null, 56% were weakly positive and 18% were strongly positive. Equivalent results for the trials were 11%, 33%, 45% and 10% respectively. Conclusions: Comorbidity correlations are generally similar in both the trials and community, providing some evidence for the reporting of comorbidity-specific findings from clinical trials.

Metabolic-associated fatty liver disease is associated with colorectal adenomas in young and older Korean adults.

BACKGROUND AND AIMS: Given that the majority of colorectal cancers (CRCs) develop from high-risk adenomas, identifying risk factors for high-risk adenomas is important. The relationship between metabolic dysfunction-associated fatty liver disease (MAFLD) and the risk of colorectal adenoma in young adults remains unclear. We aimed to evaluate this relationship in adults <50 (younger) and ≥50 (older) years of age. METHODS: This cross-sectional study included 184 792 Korean adults (80% <50 years of age) who all underwent liver ultrasound and colonoscopy. Participants were grouped into those with and without MAFLD and classified by adenoma presence into no adenoma, low-risk adenoma, or high-risk adenoma (defined as ≥3 adenomas, any ≥10 mm, or adenoma with high-grade dysplasia/villous features). RESULTS: The prevalence of low- and high-risk adenomas among young and older adults was 9.6% and 0.8% and 22.3% and 4.8%, respectively. MAFLD was associated with an increased prevalence of low- and high-risk adenomas in young and older adults. Young adults with MAFLD had a 1.30 (95% CIs 1.26-1.35) and 1.40 (1.23-1.59) times higher prevalence of low- and high-risk adenomas, respectively, compared to those without MAFLD. These associations were consistent even in lean adults (BMI < 23 kg/m2 ) and those without a family history of CRC. CONCLUSIONS: MAFLD is associated with an increased prevalence of low- and high-risk adenomas in Korean adults, regardless of age or obesity status. Whether reducing metabolic risk factors, such as MAFLD, reduces the risk of precancerous lesions and ultimately reduces the risk of early-onset CRC requires further investigation.

Elevated Glycated Haemoglobin (HbA1c) Is Associated with an Increased Risk of Pancreatic Ductal Adenocarcinoma: A UK Biobank Cohort Study.

BACKGROUND: The role of dysglycaemia as a risk marker for Pancreatic Ductal Adenocarcinoma (PDAC) is uncertain. We investigated the relationship between glycated haemoglobin (HbA1c) and incident PDAC using a retrospective cohort study within the UK Biobank. METHODS: A study involving 499,804 participants from the UK Biobank study was undertaken. Participants were stratified by diabetes mellitus (DM) status, and then by HbA1c values < 42 mmol/mol, 42-47 mmol/mol, or ≥48 mmol/mol. Cox proportional hazard models were used to describe the association between HbA1c category (with time-varying interactions) and incident PDAC. RESULTS: PDAC occurred in 1157 participants during 11.6 (10.9-12.3) years follow up [(median (interquartile range)]. In subjects without known DM at baseline, 12 months after recruitment, the adjusted hazard ratios (aHR, 95% CI) for incident PDAC for HbA1c 42-47 mmol/mol compared to HbA1c < 42 mmol/mol (reference group) was 2.10 (1.31-3.37, p = 0.002); and was 8.55 (4.58-15.99, p < 0.001) for HbA1c ≥ 48 mmol/mol. The association between baseline HbA1c and incident PDAC attenuated with increasing duration of time of follow-up to PDAC diagnosis. CONCLUSIONS: Dysglycaemia detected by elevated HbA1c is associated with an increased risk of PDAC. The strength of the association between elevated HbA1c and incident PDAC is inversely proportional to the time from detecting dysglycaemia but remains significant for at least 60 months following HbA1c testing.

Algorithms to define diabetes type using data from administrative databases: A systematic review of the evidence.

AIMS: To find the best-performing algorithms to distinguish type 1 and type 2 diabetes in administrative data. METHODS: Embase and MEDLINE databases were searched from January 2000 until January 2023. Papers evaluating the performance of algorithms to define type 1 and type 2 diabetes by reporting diagnostic metrics against a range of reference standards were selected. Study quality was evaluated using the Quality Assessment of Diagnostic Accuracy Studies. RESULTS: Of the 24 studies meeting the eligibility criteria, 19 demonstrated a low risk of bias and low concerns about the applicability of the study population across all domains. Algorithms considering multiple diabetes diagnostic codes alone were sensitive and specific approaches to classify diabetes type (both metrics >92.1% for type 1 diabetes; >86.9% for type 2 diabetes). Among the top 10-performing algorithms to detect type 1 and type 2 diabetes, 70% and 100% featured multiple criteria, respectively. Information on insulin use was more sensitive and specific for detecting diabetes type than were criteria based on use of oral hypoglycaemic agents. CONCLUSIONS: Algorithms based on multiple diabetes diagnostic codes and insulin use are the most accurate approaches to distinguish type 1 from type 2 diabetes using administrative data. Approaches with more than one criterion may also increase sensitivity in distinguishing diabetes type.

Serum 25-Hydroxyvitamin D Levels and Risk of Colorectal Cancer: An Age-Stratified Analysis.

BACKGROUND & AIMS: The role of circulating 25-hydroxyvitamin D (25(OH)D) in the prevention of early-onset colorectal cancer (CRC) in young adults aged <50 years is uncertain. We evaluated the age-stratified associations (<50 vs ≥50 years) between circulating 25(OH)D levels and the risk of CRC in a large sample of Korean adults. METHODS: Our cohort study included 236,382 participants (mean age, 38.0 [standard deviation, 9.0] years) who underwent a comprehensive health examination, including measurement of serum 25(OH)D levels. Serum 25(OH)D levels were categorized as <10, 10 to 20, and ≥20 ng/mL. CRC, along with the histologic subtype, site, and invasiveness, was ascertained through linkage with the national cancer registry. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CRC according to the serum 25(OH)D status, with adjustment for potential confounders. RESULTS: During the 1,393,741 person-years of follow-up (median, 6.5 years; interquartile range, 4.5-7.5 years), 341 participants developed CRC (incidence rate, 19.2 per 105 person-years). Among young individuals aged <50 years, serum 25(OH)D levels were inversely associated with the risk of incident CRC with HRs (95% CIs) of 0.61 (0.43-0.86) and 0.41 (0.27-0.63) for 25(OH)D 10 to 19 ng/mL and ≥20 ng/mL, respectively, with respect to the reference (<10 ng/mL) (P for trend <.001, time-dependent model). Significant associations were evident for adenocarcinoma, colon cancer, and invasive cancers. For those aged ≥50 years, associations were similar, although slightly attenuated compared with younger individuals. CONCLUSIONS: Serum 25(OH)D levels may have beneficial associations with the risk of developing CRC for both early-onset and late-onset disease.

Treatment effect modification due to comorbidity: Individual participant data meta-analyses of 120 randomised controlled trials.

BACKGROUND: People with comorbidities are underrepresented in clinical trials. Empirical estimates of treatment effect modification by comorbidity are lacking, leading to uncertainty in treatment recommendations. We aimed to produce estimates of treatment effect modification by comorbidity using individual participant data (IPD). METHODS AND FINDINGS: We obtained IPD for 120 industry-sponsored phase 3/4 trials across 22 index conditions (n = 128,331). Trials had to be registered between 1990 and 2017 and have recruited ≥300 people. Included trials were multicentre and international. For each index condition, we analysed the outcome most frequently reported in the included trials. We performed a two-stage IPD meta-analysis to estimate modification of treatment effect by comorbidity. First, for each trial, we modelled the interaction between comorbidity and treatment arm adjusted for age and sex. Second, for each treatment within each index condition, we meta-analysed the comorbidity-treatment interaction terms from each trial. We estimated the effect of comorbidity measured in 3 ways: (i) the number of comorbidities (in addition to the index condition); (ii) presence or absence of the 6 commonest comorbid diseases for each index condition; and (iii) using continuous markers of underlying conditions (e.g., estimated glomerular filtration rate (eGFR)). Treatment effects were modelled on the usual scale for the type of outcome (absolute scale for numerical outcomes, relative scale for binary outcomes). Mean age in the trials ranged from 37.1 (allergic rhinitis trials) to 73.0 (dementia trials) and percentage of male participants range from 4.4% (osteoporosis trials) to 100% (benign prostatic hypertrophy trials). The percentage of participants with 3 or more comorbidities ranged from 2.3% (allergic rhinitis trials) to 57% (systemic lupus erythematosus trials). We found no evidence of modification of treatment efficacy by comorbidity, for any of the 3 measures of comorbidity. This was the case for 20 conditions for which the outcome variable was continuous (e.g., change in glycosylated haemoglobin in diabetes) and for 3 conditions in which the outcomes were discrete events (e.g., number of headaches in migraine). Although all were null, estimates of treatment effect modification were more precise in some cases (e.g., sodium-glucose co-transporter-2 (SGLT2) inhibitors for type 2 diabetes-interaction term for comorbidity count 0.004, 95% CI -0.01 to 0.02) while for others credible intervals were wide (e.g., corticosteroids for asthma-interaction term -0.22, 95% CI -1.07 to 0.54). The main limitation is that these trials were not designed or powered to assess variation in treatment effect by comorbidity, and relatively few trial participants had >3 comorbidities. CONCLUSIONS: Assessments of treatment effect modification rarely consider comorbidity. Our findings demonstrate that for trials included in this analysis, there was no empirical evidence of treatment effect modification by comorbidity. The standard assumption used in evidence syntheses is that efficacy is constant across subgroups, although this is often criticised. Our findings suggest that for modest levels of comorbidities, this assumption is reasonable. Thus, trial efficacy findings can be combined with data on natural history and competing risks to assess the likely overall benefit of treatments in the context of comorbidity.

Iron status and cardiometabolic risk in children.

AIM: We aimed to evaluate associations between serum ferritin and transferrin and variables related to the metabolic syndrome (MetS) in children. METHODS: Cross-sectional and longitudinal study in prepubertal children (n = 832) aged 3-14 years. A subset (n = 203) were re-examined after a mean follow-up of 3.7 ± 0.8 years[range 2-6]. Outcomes were MetS and MetS components scores, glycosylated haemoglobin (HbA1c), and their follow-up change. RESULTS: Children with low ferritin had increased HbA1c Z scores (ANCOVA, P = 0.003). Ferritin was inversely associated with glycaemia [fully adjusted ß (95% confidence interval): -2.35(-4.36 to -0.34)]. Transferrin was associated with diastolic blood pressure [ß: 0.02(0.01-0.04)] and log-HOMA-IR [ß:0.001(0.0005-0.002)]. MetS risk score worsened during follow-up in children with the lowest baseline ferritin levels. In contrast, at baseline ferritin was positively associated with all (except glycaemia) the MetS-related variables but adjustments for inflammatory, hepatic function, and body mass markers attenuated those associations (P > 0.05). CONCLUSIONS: Lower iron status was independently associated with glycaemic markers and MetS in children, whereas higher ferritin levels were related to other cardiometabolic risk markers under the influence of inflammation, hepatic injury and body mass. Research is required to study whether this mixed pattern is part of an early risk or would be explained by a normal transition during growth and development.