Pub Date : 2024-03-16DOI: 10.1101/2024.03.15.24303590
Robert J Massey, Adem Y Dawed, Yu Chen, Marine Panova-Noeva, Michaela Mattheus, Moneeza K Siddiqui, Nanette Cathrin Schloot, Antonio Ceriello, Ewan R Pearson
Aims: BMI variability has been associated with increased cardiovascular disease risk in individuals with type 2 diabetes, however comparison between clinical studies and real–world observational evidence has been lacking. Furthermore, it is not known whether BMI variability has an effect independent of HbA1c variability. Methods and Results: We investigated the association between BMI variability and 3P–MACE risk in the Harmony Outcomes trial (n = 9198), and further analysed placebo arms of REWIND (n = 4440) and EMPA–REG OUTCOME (n = 2333) trials, followed by real–world data from the Tayside Bioresource (n = 6980) using Cox regression modelling. BMI variability was determined using average successive variability (ASV), with first major adverse cardiovascular event of non–fatal stroke, non–fatal myocardial infarction, and cardiovascular death (3P-MACE) as the primary outcome. After adjusting for cardiovascular risk factors, a +1 SD increase in BMI variability was associated with increased 3P–MACE risk in Harmony Outcomes (HR 1.12, 95% CI 1.08 — 1.17, P < 0.001). The most variable quartile of participants experienced an 87% higher risk of 3P-MACE (P <0.001) relative to the least variable. Similar associations were found in REWIND and Tayside Bioresource. Further analyses in the EMPA–REG OUTCOME trial did not replicate this association. BMI variability's impact on 3P–MACE risk was independent of HbA1c variability. Conclusion: In individuals with type 2 diabetes, increased BMI variability was found to be an independent risk factor for 3P–MACE across cardiovascular outcome trials and real–world datasets. Future research should attempt to establish a causal relationship between BMI variability and cardiovascular outcomes.
{"title":"BMI Variability and Cardiovascular Outcomes Within Clinical Trial and Real-World Environments in Type 2 Diabetes: An IMI2 SOPHIA study","authors":"Robert J Massey, Adem Y Dawed, Yu Chen, Marine Panova-Noeva, Michaela Mattheus, Moneeza K Siddiqui, Nanette Cathrin Schloot, Antonio Ceriello, Ewan R Pearson","doi":"10.1101/2024.03.15.24303590","DOIUrl":"https://doi.org/10.1101/2024.03.15.24303590","url":null,"abstract":"Aims:\u0000BMI variability has been associated with increased cardiovascular disease risk in individuals with type 2 diabetes, however comparison between clinical studies and real–world observational evidence has been lacking. Furthermore, it is not known whether BMI variability has an effect independent of HbA1c variability.\u0000Methods and Results:\u0000We investigated the association between BMI variability and 3P–MACE risk in the Harmony Outcomes trial (n = 9198), and further analysed placebo arms of REWIND (n = 4440) and EMPA–REG OUTCOME (n = 2333) trials, followed by real–world data from the Tayside Bioresource (n = 6980) using Cox regression modelling. BMI variability was determined using average successive variability (ASV), with first major adverse cardiovascular event of non–fatal stroke, non–fatal myocardial infarction, and cardiovascular death (3P-MACE) as the primary outcome.\u0000After adjusting for cardiovascular risk factors, a +1 SD increase in BMI variability was associated with increased 3P–MACE risk in Harmony Outcomes (HR 1.12, 95% CI 1.08 — 1.17, P < 0.001). The most variable quartile of participants experienced an 87% higher risk of 3P-MACE (P <0.001) relative to the least variable. Similar associations were found in REWIND and Tayside Bioresource. Further analyses in the EMPA–REG OUTCOME trial did not replicate this association. BMI variability's impact on 3P–MACE risk was independent of HbA1c variability.\u0000Conclusion: In individuals with type 2 diabetes, increased BMI variability was found to be an independent risk factor for 3P–MACE across cardiovascular outcome trials and real–world datasets. Future research should attempt to establish a causal relationship between BMI variability and cardiovascular outcomes.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140153466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-16DOI: 10.1101/2024.03.15.24304346
Luis Jesuino de Oliveira Andrade, Gabriela Correia Matos de Oliveira, Luisa Correia Matos de Oliveira, Alcina Maria Vinhaes Bittencourt, Luis Matos de Oliveira
Introduction: Hashimoto Thyroiditis (HT) is a prevalent autoimmune disorder impacting thyroid function. Early detection allows for timely intervention and improved patient outcomes. Traditional diagnostic methods rely on clinical presentation and antibody testing, lacking a robust risk prediction tool. Objective: To develop a high-precision machine learning (ML) model for predicting the risk of HT development. Method: Data patients were acquired from PubMed. A binary classifier was constructed through data pre-processing, feature selection, and exploration of various ML models. Hyperparameter optimization and performance evaluation metrics (AUC-ROC, AUC-PR, sensitivity, specificity, precision, F1 score) were employed. Results: Out of a total of 9,173 individuals, 400 subjects within this cohort exhibited normal thyroid function, while 436 individuals were diagnosed with HT. The mean patient age was 45 years, and 90% were female. The best performing model achieved an AUC-ROC of 0.87 and AUC-PR of 0.85, indicating high predictive accuracy. Additionally, sensitivity, specificity, precision, and F1 score reached 85%, 90%, 80%, and 83% respectively, demonstrating the model's effectiveness in identifying individuals at risk of HT development. Hyperparameter tuning was optimized using a Random Search approach. Conclusion: This study demonstrates the feasibility of utilizing ML for accurate prediction of HT risk. The high performance metrics achieved highlight the potential for this approach to become a valuable clinical tool for early identification and risk stratification of patients susceptible to HT. Keywords: Hashimoto Thyroiditis, Machine Learning, Risk Prediction, Algorithms.
简介桥本氏甲状腺炎（HT）是一种影响甲状腺功能的常见自身免疫性疾病。早期发现可及时干预，改善患者预后。传统的诊断方法依赖于临床表现和抗体检测，缺乏强有力的风险预测工具。目标：开发一种高精度的机器诊断方法：开发一种高精度的机器学习（ML）模型，用于预测甲状腺肿大的发病风险。方法：从 PubMed 获取患者数据。通过数据预处理、特征选择和探索各种 ML 模型，构建二元分类器。采用超参数优化和性能评估指标（AUC-ROC、AUC-PR、灵敏度、特异性、精确度、F1 分数）。结果：在总共 9,173 人中，有 400 人甲状腺功能正常，436 人被诊断为甲亢。患者平均年龄为 45 岁，90% 为女性。表现最好的模型的 AUC-ROC 为 0.87，AUC-PR 为 0.85，表明预测准确性很高。此外，灵敏度、特异性、精确度和 F1 分数分别达到了 85%、90%、80% 和 83%，表明该模型在识别高危人群方面非常有效。超参数调整采用随机搜索法进行了优化：本研究证明了利用 ML 准确预测高血压风险的可行性。所取得的高性能指标凸显了这一方法成为早期识别易患甲状腺炎患者并对其进行风险分层的宝贵临床工具的潜力：桥本氏甲状腺炎 机器学习 风险预测 算法
{"title":"Machine Learning-Based Prediction of Hashimoto Thyroiditis Development Risk","authors":"Luis Jesuino de Oliveira Andrade, Gabriela Correia Matos de Oliveira, Luisa Correia Matos de Oliveira, Alcina Maria Vinhaes Bittencourt, Luis Matos de Oliveira","doi":"10.1101/2024.03.15.24304346","DOIUrl":"https://doi.org/10.1101/2024.03.15.24304346","url":null,"abstract":"Introduction: Hashimoto Thyroiditis (HT) is a prevalent autoimmune disorder impacting thyroid function. Early detection allows for timely intervention and improved patient outcomes. Traditional diagnostic methods rely on clinical presentation and antibody testing, lacking a robust risk prediction tool. Objective: To develop a high-precision machine learning (ML) model for predicting the risk of HT development. Method: Data patients were acquired from PubMed. A binary classifier was constructed through data pre-processing, feature selection, and exploration of various ML models. Hyperparameter optimization and performance evaluation metrics (AUC-ROC, AUC-PR, sensitivity, specificity, precision, F1 score) were employed. Results: Out of a total of 9,173 individuals, 400 subjects within this cohort exhibited normal thyroid function, while 436 individuals were diagnosed with HT. The mean patient age was 45 years, and 90% were female. The best performing model achieved an AUC-ROC of 0.87 and AUC-PR of 0.85, indicating high predictive accuracy. Additionally, sensitivity, specificity, precision, and F1 score reached 85%, 90%, 80%, and 83% respectively, demonstrating the model's effectiveness in identifying individuals at risk of HT development. Hyperparameter tuning was optimized using a Random Search approach.\u0000Conclusion: This study demonstrates the feasibility of utilizing ML for accurate prediction of HT risk. The high performance metrics achieved highlight the potential for this approach to become a valuable clinical tool for early identification and risk stratification of patients susceptible to HT.\u0000Keywords: Hashimoto Thyroiditis, Machine Learning, Risk Prediction, Algorithms.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140153464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Importance Romosozumab, a novel anti-osteoporotic agent, confers marked improvement in bone mineral density; however, its cardiovascular safety remains a concern. Objective To compare the cardiovascular safety of romosozumab to bisphosphonates in patients with osteoporosis. Design A cohort study using a new-user, active comparator design. Setting Medical facilities, including clinics and hospitals, visited by a wide range of populations in Japan that are covered by a commercial administrative claims database, collected from March 4, 2019 to August 31, 2021. Participants Japanese adults aged ≥40 years who were diagnosed with osteoporosis or experienced a fragility fracture. Those who received romosozumab or bisphosphonates after the commercialization of romosozumab started in Japan (March 4, 2019) were included. Exposure A new prescription of romosozumab or bisphosphonate (based on verification of a 180-day washout period). Main Outcomes and Measures The primary outcome was the incidence rate of cardiovascular disease (consisting of myocardial infarction and stroke) within one year of prescription. Cardiovascular disease was identified by algorithms with a combination of diagnosis, medical procedure, and drug codes. Facility-level prescription preference for romosozumab was used as an instrumental variable, defined as the proportion of romosozumab prescribed at the patient's facility within 90 days prior to the index date. Results Of the 61,558 included prescriptions, 8,806 were for romosozumab and 52,752 were for bisphosphonates. The mean age of the romosozumab group was higher than that of the bisphosphonates group (80.5 vs. 78.3 years, respectively). The majority of patients were female (80.2 vs. 85.3%, respectively). The incidence of cardiovascular disease was 7.98 per 100 person-years for romosozumab versus 7.15 for bisphosphonates (unadjusted incidence rate ratio: 1.12 (95% confidence interval: 1.03-1.21)). An instrumental variable analysis using the two-stage residual inclusion method yielded a hazard ratio of 1.09 (95% confidence interval: 0.79-1.76) for romosozumab compared to bisphosphonates over one year. Conclusions and Relevance In this large observational study, there was no definitive evidence of increased risk of cardiovascular disease associated with romosozumab use compared with bisphosphonates in patients with osteoporosis. These findings alleviate clinicians' excessive concerns about the potential cardiovascular safety of romosozumab in treatment decision-making for osteoporosis.
{"title":"Comparative cardiovascular safety of romosozumab versus bisphosphonates in Japanese patients with osteoporosis A new-user, active comparator design with instrumental variable analyses","authors":"Ryoji Tominaga, Tatsuyoshi Ikenoue, Ryosuke Ishii, Kakuya Niihata, Tetsuro Aita, Tadahisa Okuda, Sayaka Shimizu, Masataka Taguri, Noriaki Kurita","doi":"10.1101/2024.03.14.24304284","DOIUrl":"https://doi.org/10.1101/2024.03.14.24304284","url":null,"abstract":"Importance\u0000Romosozumab, a novel anti-osteoporotic agent, confers marked improvement in bone mineral density; however, its cardiovascular safety remains a concern. Objective\u0000To compare the cardiovascular safety of romosozumab to bisphosphonates in patients with osteoporosis. Design\u0000A cohort study using a new-user, active comparator design. Setting\u0000Medical facilities, including clinics and hospitals, visited by a wide range of populations in Japan that are covered by a commercial administrative claims database, collected from March 4, 2019 to August 31, 2021. Participants\u0000Japanese adults aged ≥40 years who were diagnosed with osteoporosis or experienced a fragility fracture. Those who received romosozumab or bisphosphonates after the commercialization of romosozumab started in Japan (March 4, 2019) were included. Exposure\u0000A new prescription of romosozumab or bisphosphonate (based on verification of a 180-day washout period). Main Outcomes and Measures\u0000The primary outcome was the incidence rate of cardiovascular disease (consisting of myocardial infarction and stroke) within one year of prescription. Cardiovascular disease was identified by algorithms with a combination of diagnosis, medical procedure, and drug codes. Facility-level prescription preference for romosozumab was used as an instrumental variable, defined as the proportion of romosozumab prescribed at the patient's facility within 90 days prior to the index date. Results\u0000Of the 61,558 included prescriptions, 8,806 were for romosozumab and 52,752 were for bisphosphonates. The mean age of the romosozumab group was higher than that of the bisphosphonates group (80.5 vs. 78.3 years, respectively). The majority of patients were female (80.2 vs. 85.3%, respectively). The incidence of cardiovascular disease was 7.98 per 100 person-years for romosozumab versus 7.15 for bisphosphonates (unadjusted incidence rate ratio: 1.12 (95% confidence interval: 1.03-1.21)). An instrumental variable analysis using the two-stage residual inclusion method yielded a hazard ratio of 1.09 (95% confidence interval: 0.79-1.76) for romosozumab compared to bisphosphonates over one year. Conclusions and Relevance\u0000In this large observational study, there was no definitive evidence of increased risk of cardiovascular disease associated with romosozumab use compared with bisphosphonates in patients with osteoporosis. These findings alleviate clinicians' excessive concerns about the potential cardiovascular safety of romosozumab in treatment decision-making for osteoporosis.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140153477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1101/2024.03.14.24304281
Flavia Costi, Darian Onchis, Eduard Hogea, Codruta Istin
The purpose of this paper is to present a detailed investigation of the advantages of employing GraphLIME (Local Interpretable Model Explanations for Graph Neural Networks) for the trustworthy prediction of diabetes mellitus. Our pursuit involves identifying the strengths of GraphLIME combined with the attention-mechanism over the standard coupling of deep learning neural networks with the original LIME method. The system build this way, provided us a proficient method for extracting the most relevant features and applying the attention mechanism exclusively to those features. We have closely monitored the performance metrics of the two approaches and conducted a comparative analysis. Leveraging attention mechanisms, we have achieved an accuracy of 92.6% for the addressed problem. The model's performance is meticulously demonstrated throughout the study, and the results are furthermore evaluated using the Receiver Operating Characteristic (ROC) curve. By implementing this technique on a dataset of 768 patients diagnosed with or without diabetes mellitus, we have successfully boosted the model's performance by over 18%.
{"title":"Predictive Modeling for Diabetes Using GraphLIME","authors":"Flavia Costi, Darian Onchis, Eduard Hogea, Codruta Istin","doi":"10.1101/2024.03.14.24304281","DOIUrl":"https://doi.org/10.1101/2024.03.14.24304281","url":null,"abstract":"The purpose of this paper is to present a detailed investigation of the advantages of employing GraphLIME (Local Interpretable Model Explanations for Graph Neural Networks) for the trustworthy prediction of diabetes mellitus. Our pursuit involves identifying the strengths of GraphLIME combined with the attention-mechanism over the standard coupling of deep learning neural networks with the original LIME method. The system build this way, provided us a proficient method for extracting the most relevant features and applying the attention mechanism exclusively to those features. We have closely monitored the performance metrics of the two approaches and conducted a comparative analysis. Leveraging attention mechanisms, we have achieved an accuracy of 92.6% for the addressed problem. The model's performance is meticulously demonstrated throughout the study, and the results are furthermore evaluated using the Receiver Operating Characteristic (ROC) curve. By implementing this technique on a dataset of 768 patients diagnosed with or without diabetes mellitus, we have successfully boosted the model's performance by over 18%.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140153473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1101/2024.03.10.24304039
Itai M Magodoro, Aloice Aluoch, Brian Claggett, Moffat J. Nyirenda, Mark J Siedner, Katalin Andrea A Wilkinson, Robert J Wilkinson, Ntobeko AB Ntusi
Type 2 diabetes mellitus (T2DM) may be a long-term sequela of infection with Mycobacterium tuberculosis (M.tb) by mechanisms that remain to be fully explained. We evaluated the association between M.tb sensitization and T2DM among U.S adults and, via formal mediation analysis, the extent to which this association is mediated by insulin resistance and/or β-cell failure. These evaluations accounted for demographic, socio-economic, behavioral and clinical characteristics. T2DM was assessed by fasting plasma glucose, 2-hour oral glucose tolerance testing and HbA1c; homoeostasis model assessment 2 (HOMA2) was used to estimate β-cell dysfunction (HOMA2-B) and insulin resistance (HOMA2-IR); while M.tb sensitization status was ascertained by tuberculin skin testing (TST). Exposure to M.tb was associated with increased risk for T2DM, likely driven by an increase in insulin resistance. Definitive prospective studies examining incident T2DM following tuberculosis are warranted.
{"title":"Insulin resistance, and not β-cell impairment, mediates association between Mycobacterium tuberculosis sensitization and type II diabetes mellitus among US adults.","authors":"Itai M Magodoro, Aloice Aluoch, Brian Claggett, Moffat J. Nyirenda, Mark J Siedner, Katalin Andrea A Wilkinson, Robert J Wilkinson, Ntobeko AB Ntusi","doi":"10.1101/2024.03.10.24304039","DOIUrl":"https://doi.org/10.1101/2024.03.10.24304039","url":null,"abstract":"Type 2 diabetes mellitus (T2DM) may be a long-term sequela of infection with Mycobacterium tuberculosis (M.tb) by mechanisms that remain to be fully explained. We evaluated the association between M.tb sensitization and T2DM among U.S adults and, via formal mediation analysis, the extent to which this association is mediated by insulin resistance and/or β-cell failure. These evaluations accounted for demographic, socio-economic, behavioral and clinical characteristics. T2DM was assessed by fasting plasma glucose, 2-hour oral glucose tolerance testing and HbA1c; homoeostasis model assessment 2 (HOMA2) was used to estimate β-cell dysfunction (HOMA2-B) and insulin resistance (HOMA2-IR); while M.tb sensitization status was ascertained by tuberculin skin testing (TST). Exposure to M.tb was associated with increased risk for T2DM, likely driven by an increase in insulin resistance. Definitive prospective studies examining incident T2DM following tuberculosis are warranted.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140153484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-14DOI: 10.1101/2024.03.10.24304033
Itai M Magodoro, Alison C castle, Ndumiso Tshuma, Julia H. Goedecke, Ronel Sewpaul, Justen Manasa, Jennifer Manne-Goehler, Ntobeko AB Ntusi, Mark J Siedner
It is unclear how rising obesity among people with HIV (PWH) in sub-Saharan Africa (SSA) impacts their risk of type 2 diabetes mellitus (diabetes). Using a South African national cross-sectional sample of adult PWH and their peers without HIV (PWOH), we examined the associations between HIV and prevalent diabetes across the spectrum of body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WtHR). Analyses were sex stratified, and adjusted for age, sociodemographic and behavioral factors. The prevalence of diabetes among males was similar between PWH and PWOH, overall and at all levels of adiposity. In contrast, overall diabetes prevalence was higher among female PWOH than female PWH. However, there also were differences according to adiposity such that, compared to female PWOH, relative diabetes prevalence in female PWH was reduced with obesity but accentuated with leanness. These differences in the relationship between adiposity and diabetes by HIV serostatus call for better mechanistic understanding of sex-specific adipose tissue biology in HIV in South Africa, and possibly in other HIV endemic settings in SSA.
{"title":"Associations of HIV and prevalent type 2 diabetes mellitus in the context of obesity in South Africa.","authors":"Itai M Magodoro, Alison C castle, Ndumiso Tshuma, Julia H. Goedecke, Ronel Sewpaul, Justen Manasa, Jennifer Manne-Goehler, Ntobeko AB Ntusi, Mark J Siedner","doi":"10.1101/2024.03.10.24304033","DOIUrl":"https://doi.org/10.1101/2024.03.10.24304033","url":null,"abstract":"It is unclear how rising obesity among people with HIV (PWH) in sub-Saharan Africa (SSA) impacts their risk of type 2 diabetes mellitus (diabetes). Using a South African national cross-sectional sample of adult PWH and their peers without HIV (PWOH), we examined the associations between HIV and prevalent diabetes across the spectrum of body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WtHR). Analyses were sex stratified, and adjusted for age, sociodemographic and behavioral factors. The prevalence of diabetes among males was similar between PWH and PWOH, overall and at all levels of adiposity. In contrast, overall diabetes prevalence was higher among female PWOH than female PWH. However, there also were differences according to adiposity such that, compared to female PWOH, relative diabetes prevalence in female PWH was reduced with obesity but accentuated with leanness. These differences in the relationship between adiposity and diabetes by HIV serostatus call for better mechanistic understanding of sex-specific adipose tissue biology in HIV in South Africa, and possibly in other HIV endemic settings in SSA.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140153557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1101/2024.03.10.24304052
Anna Tichler, Dorijn F.L. Hertroijs, Ghislaine A.P.G. van Mastrigt, Martijn C.G.J. Brouwers, Dirk Ruwaard, Arianne M.J. Elissen
Introduction We developed a multistage shared decision-making program for type 2 diabetes that aims to support person-centered type 2 diabetes management in primary care. The program consists of an online patient decision aid, a preparatory consult for patients, and interprofessional training for healthcare professionals. The short- and long-term effectiveness of the multistage shared decision-making program needs to be researched in a trial-based economic evaluation. To evaluate the feasibility of study methods for future economic evaluation, we will conduct a pilot study that focuses on sample recruitment and retention, study management, and feasibility of outcome and cost measurements. Methods and analysis The multistage shared decision-making program will be pilot-tested in a cluster-randomized controlled trial in four primary care practices (located in the region of Gorinchem, the Netherlands) using a mixed-methods approach. The intervention practices will adopt the program, whereas the control practices provide usual care. Data collection will include recruitment, retention, and consent rates, patients’ sociodemographic and clinical characteristics, and the assessment of primary and secondary outcomes of the future trial-based economic evaluation. We will also collect data on the usage behavior of patients when completing questionnaires of the primary and secondary outcomes (i.e. time needed to complete questionnaires). Semi-structured interviews with patients will be conducted to obtain insights into the understandability and usability of measurement tools. Moreover, focus groups with healthcare professionals from participating practices will be organized to complement the quantitative data on sample representativeness and to assess the study management challenges of participating practices. Discussion The pilot will address uncertainties around the feasibility of a future trial-based economic evaluation, focusing on sample recruitment and retention, study management, and the feasibility of outcome and cost measurements. The results will guide the improvement of study procedures for the economic evaluation of our multistage shared decision-making program for type 2 diabetes.
{"title":"Evaluating the feasibility of study methods for a future trial-based economic evaluation of a multistage shared decision-making program for type 2 diabetes mellitus: protocol for a cluster-randomized controlled pilot study","authors":"Anna Tichler, Dorijn F.L. Hertroijs, Ghislaine A.P.G. van Mastrigt, Martijn C.G.J. Brouwers, Dirk Ruwaard, Arianne M.J. Elissen","doi":"10.1101/2024.03.10.24304052","DOIUrl":"https://doi.org/10.1101/2024.03.10.24304052","url":null,"abstract":"Introduction We developed a multistage shared decision-making program for type 2 diabetes that aims to support person-centered type 2 diabetes management in primary care. The program consists of an online patient decision aid, a preparatory consult for patients, and interprofessional training for healthcare professionals. The short- and long-term effectiveness of the multistage shared decision-making program needs to be researched in a trial-based economic evaluation. To evaluate the feasibility of study methods for future economic evaluation, we will conduct a pilot study that focuses on sample recruitment and retention, study management, and feasibility of outcome and cost measurements. Methods and analysis The multistage shared decision-making program will be pilot-tested in a cluster-randomized controlled trial in four primary care practices (located in the region of Gorinchem, the Netherlands) using a mixed-methods approach. The intervention practices will adopt the program, whereas the control practices provide usual care. Data collection will include recruitment, retention, and consent rates, patients’ sociodemographic and clinical characteristics, and the assessment of primary and secondary outcomes of the future trial-based economic evaluation. We will also collect data on the usage behavior of patients when completing questionnaires of the primary and secondary outcomes (i.e. time needed to complete questionnaires). Semi-structured interviews with patients will be conducted to obtain insights into the understandability and usability of measurement tools. Moreover, focus groups with healthcare professionals from participating practices will be organized to complement the quantitative data on sample representativeness and to assess the study management challenges of participating practices. Discussion The pilot will address uncertainties around the feasibility of a future trial-based economic evaluation, focusing on sample recruitment and retention, study management, and the feasibility of outcome and cost measurements. The results will guide the improvement of study procedures for the economic evaluation of our multistage shared decision-making program for type 2 diabetes.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"167 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140127879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1101/2024.03.11.24304084
Elise J Needham, Janne R. Hingst, Johan D. Onslev, Alexis Diaz-Vegas, Magnus R. Leandersson, Kristen Cooke, Guang Yang, Jonas M. Kristensen, Kohei Kido, Benjamin L. Parker, Kurt Højlund, Erik A. Richter, Christian Pehmøller, Sean J. Humphrey, David E. James, Jørgen F.P. Wojtaszewski
Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters signalling responses in skeletal muscle and how this is modified by exercise. We measured parallel phenotypes and phosphoproteomes of insulin resistant and insulin sensitive individuals as they responded to exercise and insulin (n=19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Our personalized phosphoproteomics approach revealed that insulin resistant individuals have selective and time-dependent signalling alterations. Insulin resistant subjects have reduced insulin-stimulated mTORC1 responses and alterations to non-canonical rather than canonical insulin signalling. Prior exercise promotes insulin sensitivity even in insulin resistant individuals by priming a portion of insulin signalling prior to insulin infusion. This includes MINDY1 S441, which is elevated in insulin-sensitive subjects and primed by prior exercise. MINDY1 contains a missense variant that is protective for type 2 diabetes but its role in disease risk is unknown. We show that MINDY1 S441 phosphorylation is downstream of AKT, and MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signalling alterations in insulin resistant skeletal muscle and how exercise partially counteracts these and identifies MINDY1 as a regulator of insulin action.
{"title":"Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action","authors":"Elise J Needham, Janne R. Hingst, Johan D. Onslev, Alexis Diaz-Vegas, Magnus R. Leandersson, Kristen Cooke, Guang Yang, Jonas M. Kristensen, Kohei Kido, Benjamin L. Parker, Kurt Højlund, Erik A. Richter, Christian Pehmøller, Sean J. Humphrey, David E. James, Jørgen F.P. Wojtaszewski","doi":"10.1101/2024.03.11.24304084","DOIUrl":"https://doi.org/10.1101/2024.03.11.24304084","url":null,"abstract":"Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters signalling responses in skeletal muscle and how this is modified by exercise. We measured parallel phenotypes and phosphoproteomes of insulin resistant and insulin sensitive individuals as they responded to exercise and insulin (n=19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Our personalized phosphoproteomics approach revealed that insulin resistant individuals have selective and time-dependent signalling alterations. Insulin resistant subjects have reduced insulin-stimulated mTORC1 responses and alterations to non-canonical rather than canonical insulin signalling. Prior exercise promotes insulin sensitivity even in insulin resistant individuals by priming a portion of insulin signalling prior to insulin infusion. This includes MINDY1 S441, which is elevated in insulin-sensitive subjects and primed by prior exercise. MINDY1 contains a missense variant that is protective for type 2 diabetes but its role in disease risk is unknown. We show that MINDY1 S441 phosphorylation is downstream of AKT, and MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signalling alterations in insulin resistant skeletal muscle and how exercise partially counteracts these and identifies MINDY1 as a regulator of insulin action.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140127538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1101/2024.03.11.24304115
Sara Andrea Metzger, Grit Sommer, Christa E Flueck, Swiss DSD Cohort Study Group
Objective: Reliable data on prevalence of rare differences of sex development (DSD) are lacking. We aimed to estimate population-based prevalence of DSD in Switzerland. Design: Retrospective population-based study including individuals with DSD according to Chicago Consensus, born in Switzerland from 2000-2019. Methods: Endocrine care centers in all ten Swiss Children's Hospitals and eight private endocrine practices collected DSD data through the I-DSD registry or case report forms. We calculated prevalence for DSD diagnostic groups and analyzed time trends in prevalence. Results: Over the 20-year study period, we identified 561 individuals with DSD. Almost half (n=266, 47%) had sex chromosome DSD, 177 (32%) had 46,XY DSD and 118 (21%) had 46, XX DSD. Causes for 46,XY DSD were disturbed androgen synthesis or action (37/177, 21%), atypical gonadal development (28/177, 16%), or other causes (112/177, 63%). Causes for 46,XX DSD were androgen excess (99/118, 84%), atypical gonadal development (8/118, 7%), or other causes (11/118, 9%). On average, 28 new cases were born with DSD annually. Prevalence was 17 for sex chromosome DSD, 12 for 46,XY DSD and 8 for 46,XX DSD per 100'000 live births and year. One per 7'500 newborn girls had 46,XX congenital adrenal hypoplasia (CAH). Conclusion: Prevalence of sex chromosome DSD was lower than expected because of underreporting due to late diagnosis. Prevalence of 46,XX CAH is similar to newborn screening data, suggesting good completeness of cases. For complex DSD cases, we expect complete coverage. This study provides a valuable resource for policymaking and (inter)national research on DSD.
{"title":"Prevalence of differences of sex development in Switzerland from 2000-2019","authors":"Sara Andrea Metzger, Grit Sommer, Christa E Flueck, Swiss DSD Cohort Study Group","doi":"10.1101/2024.03.11.24304115","DOIUrl":"https://doi.org/10.1101/2024.03.11.24304115","url":null,"abstract":"Objective: Reliable data on prevalence of rare differences of sex development (DSD) are lacking. We aimed to estimate population-based prevalence of DSD in Switzerland.\u0000Design: Retrospective population-based study including individuals with DSD according to Chicago Consensus, born in Switzerland from 2000-2019.\u0000Methods: Endocrine care centers in all ten Swiss Children's Hospitals and eight private endocrine practices collected DSD data through the I-DSD registry or case report forms. We calculated prevalence for DSD diagnostic groups and analyzed time trends in prevalence. Results: Over the 20-year study period, we identified 561 individuals with DSD. Almost half (n=266, 47%) had sex chromosome DSD, 177 (32%) had 46,XY DSD and 118 (21%) had 46, XX DSD. Causes for 46,XY DSD were disturbed androgen synthesis or action (37/177, 21%), atypical gonadal development (28/177, 16%), or other causes (112/177, 63%). Causes for 46,XX DSD were androgen excess (99/118, 84%), atypical gonadal development (8/118, 7%), or other causes (11/118, 9%). On average, 28 new cases were born with DSD annually. Prevalence was 17 for sex chromosome DSD, 12 for 46,XY DSD and 8 for 46,XX DSD per 100'000 live births and year. One per 7'500 newborn girls had 46,XX congenital adrenal hypoplasia (CAH).\u0000Conclusion: Prevalence of sex chromosome DSD was lower than expected because of underreporting due to late diagnosis. Prevalence of 46,XX CAH is similar to newborn screening data, suggesting good completeness of cases. For complex DSD cases, we expect complete coverage. This study provides a valuable resource for policymaking and (inter)national research on DSD.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"167 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140127834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-09DOI: 10.1101/2024.03.08.24303962
Luise Müller, Anne Hoffmann, Stephan H. Bernhart, Adhideb Ghosh, Jiawei Zhong, Tobias Hagemann, Wenfei Sun, Hua Dong, Falko Noé, Christian Wolfrum, Arne Dietrich, Michael Stumvoll, Lucas Massier, Matthias Blüher, Peter Kovacs, Rima Chakaroun, Maria Keller
Background Studies on DNA methylation following bariatric surgery have primarily focused on blood cells, while it is unclear to which extend it may reflect DNA methylation profiles in specific metabolically relevant organs such as adipose tissue (AT). Here, we investigated whether adipose tissue depots specific methylation changes after bariatric surgery are mirrored in blood. Methods Using Illumina 850K EPIC technology, we analysed genome-wide DNA methylation in paired blood, subcutaneous and omental visceral AT (SAT/OVAT) samples from nine individuals with severe obesity pre- and post-surgery. Findings The numbers and effect sizes of differentially methylated regions (DMRs) post-bariatric surgery were more pronounced in AT (SAT: 12,865 DMRs from -11.5 to 10.8%; OVAT: 14,632 DMRs from -13.7 to 12.8%) than in blood (9,267 DMRs from -8.8 to 7.7%). Cross-tissue DMRs implicated immune-related genes. Among them, 49 regions could be validated with similar methylation changes in blood from independent individuals. Fourteen DMRs correlated with differentially expressed genes in AT post bariatric surgery, including downregulation of PIK3AP1 in both SAT and OVAT. DNA methylation age acceleration was significantly higher in AT compared to blood, but remained unaffected after surgery. Interpretation Concurrent methylation pattern changes in blood and AT, particularly in immune-related genes, suggest blood DNA methylation mirrors inflammatory state of AT post-bariatric surgery.
背景有关减肥手术后 DNA 甲基化的研究主要集中在血细胞上，目前还不清楚它在多大程度上反映了特定代谢相关器官（如脂肪组织）的 DNA 甲基化情况。在此，我们研究了减肥手术后脂肪组织库的特定甲基化变化是否反映在血液中。方法利用 Illumina 850K EPIC 技术，我们分析了九名重度肥胖患者手术前后配对血液、皮下和网膜内脏脂肪组织（SAT/OVAT）样本的全基因组 DNA 甲基化情况。研究结果减肥手术后内脏AT（SAT：12,865个DMRs，从-11.5%到10.8%；OVAT：14,632个DMRs，从-13.7%到12.8%）不同甲基化区域（DMRs）的数量和效应大小比血液（9,267个DMRs，从-8.8%到7.7%）更明显。跨组织 DMRs 涉及免疫相关基因。其中，49个区域可与独立个体血液中相似的甲基化变化进行验证。14个DMRs与减肥术后AT中不同表达基因相关，包括PIK3AP1在SAT和OVAT中的下调。与血液相比，AT 的 DNA 甲基化年龄加速度明显更高，但手术后仍不受影响。
{"title":"Blood methylation pattern reflects epigenetic remodelling in adipose tissue after bariatric surgery","authors":"Luise Müller, Anne Hoffmann, Stephan H. Bernhart, Adhideb Ghosh, Jiawei Zhong, Tobias Hagemann, Wenfei Sun, Hua Dong, Falko Noé, Christian Wolfrum, Arne Dietrich, Michael Stumvoll, Lucas Massier, Matthias Blüher, Peter Kovacs, Rima Chakaroun, Maria Keller","doi":"10.1101/2024.03.08.24303962","DOIUrl":"https://doi.org/10.1101/2024.03.08.24303962","url":null,"abstract":"Background\u0000Studies on DNA methylation following bariatric surgery have primarily focused on blood cells, while it is unclear to which extend it may reflect DNA methylation profiles in specific metabolically relevant organs such as adipose tissue (AT). Here, we investigated whether adipose tissue depots specific methylation changes after bariatric surgery are mirrored in blood. Methods\u0000Using Illumina 850K EPIC technology, we analysed genome-wide DNA methylation in paired blood, subcutaneous and omental visceral AT (SAT/OVAT) samples from nine individuals with severe obesity pre- and post-surgery. Findings\u0000The numbers and effect sizes of differentially methylated regions (DMRs) post-bariatric surgery were more pronounced in AT (SAT: 12,865 DMRs from -11.5 to 10.8%; OVAT: 14,632 DMRs from -13.7 to 12.8%) than in blood (9,267 DMRs from -8.8 to 7.7%). Cross-tissue DMRs implicated immune-related genes. Among them, 49 regions could be validated with similar methylation changes in blood from independent individuals. Fourteen DMRs correlated with differentially expressed genes in AT post bariatric surgery, including downregulation of PIK3AP1 in both SAT and OVAT. DNA methylation age acceleration was significantly higher in AT compared to blood, but remained unaffected after surgery.\u0000Interpretation\u0000Concurrent methylation pattern changes in blood and AT, particularly in immune-related genes, suggest blood DNA methylation mirrors inflammatory state of AT post-bariatric surgery.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140074844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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