Sodium-based paracetamol: impact on blood pressure, cardiovascular events, and all-cause mortality.

BACKGROUND AND AIMS: Effervescent formulations of paracetamol containing sodium bicarbonate have been reported to associate with increased blood pressure and a higher risk of cardiovascular diseases and all-cause mortality. Given the major implications of these findings, the reported associations were re-examined. METHODS: Using linked electronic health records data, a cohort of 475 442 UK individuals with at least one prescription of paracetamol, aged between 60 and 90 years, was identified. Outcomes in patients taking sodium-based paracetamol were compared with those taking non-sodium-based formulations of the same. Using a deep learning approach, associations with systolic blood pressure (SBP), major cardiovascular events (myocardial infarction, heart failure, and stroke), and all-cause mortality within 1 year after baseline were investigated. RESULTS: A total of 460 980 and 14 462 patients were identified for the non-sodium-based and sodium-based paracetamol exposure groups, respectively (mean age: 74 years; 64% women). Analysis revealed no difference in SBP [mean difference -0.04 mmHg (95% confidence interval -0.51, 0.43)] and no association with major cardiovascular events [relative risk (RR) 1.03 (0.91, 1.16)]. Sodium-based paracetamol showed a positive association with all-cause mortality [RR 1.46 (1.40, 1.52)]. However, after further accounting of other sources of residual confounding, the observed association attenuated towards the null [RR 1.08 (1.01, 1.16)]. Exploratory analyses revealed dysphagia and related conditions as major sources of uncontrolled confounding by indication for this association. CONCLUSIONS: This study does not support previous suggestions of increased SBP and an elevated risk of cardiovascular events from short-term use of sodium bicarbonate paracetamol in routine clinical practice.

Biaxial hyperelastic and anisotropic behaviors of the corneal anterior central stroma along the preferential fibril orientations. Part I: Measurement and calibration of personalized stress-strain curves.

Lacking specimens is the biggest limitation of studying the mechanical behaviors of human corneal. Extracting stress-strain curves is the crucial step in investigating hyperelastic and anisotropic properties of human cornea. 15 human corneal specimens extracted from the small incision lenticule extraction (SMILE) surgery were applied in this study. To accurately measure the personalized true stress-strain curve using corneal lenticules, the digital image correlation (DIC) method and finite element method were used to calibrate the stress and the strain of the biaxial extension test. The hyperelastic load-displacement curves obtained from the biaxial extension test were performed in preferential fibril orientations, which are arranged along the nasal-temporal (NT) and the superior-inferior (SI) directions within the anterior central stroma. The displacement and strain fields were accurately calibrated and calculated using the digital image correlation (DIC) method. A conversion equation was given to convert the effective engineering strain to the true strain. The stress field distribution, which was simulated using the finite element method, was verified. Based on this, the effective nominal stress with personalized characteristics was calibrated. The personalized stress-strain curves containing individual characteristic, like diopter and anterior surface curvature, was accurately measured in this study. These results provide an experimental method using biaxial tensile test with corneal lenticules. It is the foundation for investigating the hyperelasticity and anisotropy of the central anterior stroma of human cornea.

AD-BERT: Using pre-trained language model to predict the progression from mild cognitive impairment to Alzheimer's disease.

OBJECTIVE: We develop a deep learning framework based on the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model using unstructured clinical notes from electronic health records (EHRs) to predict the risk of disease progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). METHODS: We identified 3657 patients diagnosed with MCI together with their progress notes from Northwestern Medicine Enterprise Data Warehouse (NMEDW) between 2000 and 2020. The progress notes no later than the first MCI diagnosis were used for the prediction. We first preprocessed the notes by deidentification, cleaning and splitting into sections, and then pre-trained a BERT model for AD (named AD-BERT) based on the publicly available Bio+Clinical BERT on the preprocessed notes. All sections of a patient were embedded into a vector representation by AD-BERT and then combined by global MaxPooling and a fully connected network to compute the probability of MCI-to-AD progression. For validation, we conducted a similar set of experiments on 2563 MCI patients identified at Weill Cornell Medicine (WCM) during the same timeframe. RESULTS: Compared with the 7 baseline models, the AD-BERT model achieved the best performance on both datasets, with Area Under receiver operating characteristic Curve (AUC) of 0.849 and F1 score of 0.440 on NMEDW dataset, and AUC of 0.883 and F1 score of 0.680 on WCM dataset. CONCLUSION: The use of EHRs for AD-related research is promising, and AD-BERT shows superior predictive performance in modeling MCI-to-AD progression prediction. Our study demonstrates the utility of pre-trained language models and clinical notes in predicting MCI-to-AD progression, which could have important implications for improving early detection and intervention for AD.

How Much Lowering of Blood Pressure Is Required to Prevent Cardiovascular Disease in Patients With and Without Previous Cardiovascular Disease?

PURPOSE OF REVIEW: To review the recent large-scale randomised evidence on pharmacologic reduction in blood pressure for the primary and secondary prevention of cardiovascular disease. RECENT FINDINGS: Based on findings of the meta-analysis of individual participant-level data from 48 randomised clinical trials and involving 344,716 participants with mean age of 65 years, the relative reduction in the risk of developing major cardiovascular events was proportional to the magnitude of achieved reduction in blood pressure. For each 5-mmHg reduction in systolic blood pressure, the risk of developing cardiovascular events fell by 10% (hazard ratio [HR] (95% confidence interval [CI], 0.90 [0.88 to 0.92]). When participants were stratified by their history of cardiovascular disease, the HRs (95% CI) in those with and without previous cardiovascular disease were 0.89 (0.86 to 0.92) and 0.91 (0.89 to 0.94), respectively, with no significant heterogeneity in these effects (adjusted P for interaction = 1.0). When these patient groups were further stratified by their baseline systolic blood pressure in increments of 10 mmHg from < 120 to ≥ 170 mmHg, there was no significant heterogeneity in the relative risk reduction across these categories in people with or without previous cardiovascular disease (adjusted P for interaction were 1.00 and 0.28, respectively). Pharmacologic lowering of blood pressure was effective in preventing major cardiovascular disease events both in people with or without previous cardiovascular disease, which was not modified by their baseline blood pressure level. Treatment effects were shown to be proportional to the intensity of blood pressure reduction, but even modest blood pressure reduction, on average, can lead to meaningful gains in the prevention of incident or recurrent cardiovascular disease.

Comparison between machine learning methods for mortality prediction for sepsis patients with different social determinants.

BACKGROUND: Sepsis is one of the most life-threatening circumstances for critically ill patients in the United States, while diagnosis of sepsis is challenging as a standardized criteria for sepsis identification is still under development. Disparities in social determinants of sepsis patients can interfere with the risk prediction performances using machine learning. METHODS: We analyzed a cohort of critical care patients from the Medical Information Mart for Intensive Care (MIMIC)-III database. Disparities in social determinants, including race, sex, marital status, insurance types and languages, among patients identified by six available sepsis criteria were revealed by forest plots with 95% confidence intervals. Sepsis patients were then identified by the Sepsis-3 criteria. Sixteen machine learning classifiers were trained to predict in-hospital mortality for sepsis patients on a training set constructed by random selection. The performance was measured by area under the receiver operating characteristic curve (AUC). The performance of the trained model was tested on the entire randomly conducted test set and each sub-population built based on each of the following social determinants: race, sex, marital status, insurance type, and language. The fluctuations in performances were further examined by permutation tests. RESULTS: We analyzed a total of 11,791 critical care patients from the MIMIC-III database. Within the population identified by each sepsis identification method, significant differences were observed among sub-populations regarding race, marital status, insurance type, and language. On the 5783 sepsis patients identified by the Sepsis-3 criteria statistically significant performance decreases for mortality prediction were observed when applying the trained machine learning model on Asian and Hispanic patients, as well as the Spanish-speaking patients. With pairwise comparison, we detected performance discrepancies in mortality prediction between Asian and White patients, Asians and patients of other races, as well as English-speaking and Spanish-speaking patients. CONCLUSIONS: Disparities in proportions of patients identified by various sepsis criteria were detected among the different social determinant groups. The performances of mortality prediction for sepsis patients can be compromised when applying a universally trained model for each subpopulation. To achieve accurate diagnosis, a versatile diagnostic system for sepsis is needed to overcome the social determinant disparities of patients.

Association between cardiometabolic disease multimorbidity and all-cause mortality in 2 million women and men registered in UK general practices.

BACKGROUND: Myocardial infarction (MI), stroke and diabetes share underlying risk factors and commonalities in clinical management. We examined if their combined impact on mortality is proportional, amplified or less than the expected risk separately of each disease and whether the excess risk is explained by their associated comorbidities. METHODS: Using large-scale electronic health records, we identified 2,007,731 eligible patients (51% women) and registered with general practices in the UK and extracted clinical information including diagnosis of myocardial infarction (MI), stroke, diabetes and 53 other long-term conditions before 2005 (study baseline). We used Cox regression to determine the risk of all-cause mortality with age as the underlying time variable and tested for excess risk due to interaction between cardiometabolic conditions. RESULTS: At baseline, the mean age was 51 years, and 7% (N = 145,910) have had a cardiometabolic condition. After a 7-year mean follow-up, 146,994 died. The sex-adjusted hazard ratios (HR) (95% confidence interval [CI]) of all-cause mortality by baseline disease status, compared to those without cardiometabolic disease, were MI = 1.51 (1.49-1.52), diabetes = 1.52 (1.51-1.53), stroke = 1.84 (1.82-1.86), MI and diabetes = 2.14 (2.11-2.17), MI and stroke = 2.35 (2.30-2.39), diabetes and stroke = 2.53 (2.50-2.57) and all three = 3.22 (3.15-3.30). Adjusting for other concurrent comorbidities attenuated these estimates, including the risk associated with having all three conditions (HR = 1.81 [95% CI 1.74-1.89]). Excess risks due to interaction between cardiometabolic conditions, particularly when all three conditions were present, were not significantly greater than expected from the individual disease effects. CONCLUSION: Myocardial infarction, stroke and diabetes were associated with excess mortality, without evidence of any amplification of risk in people with all three diseases. The presence of other comorbidities substantially contributed to the excess mortality risks associated with cardiometabolic disease multimorbidity.

Using Tweets to Understand How COVID-19-Related Health Beliefs Are Affected in the Age of Social Media: Twitter Data Analysis Study.

BACKGROUND: The emergence of SARS-CoV-2 (ie, COVID-19) has given rise to a global pandemic affecting 215 countries and over 40 million people as of October 2020. Meanwhile, we are also experiencing an infodemic induced by the overabundance of information, some accurate and some inaccurate, spreading rapidly across social media platforms. Social media has arguably shifted the information acquisition and dissemination of a considerably large population of internet users toward higher interactivities. OBJECTIVE: This study aimed to investigate COVID-19-related health beliefs on one of the mainstream social media platforms, Twitter, as well as potential impacting factors associated with fluctuations in health beliefs on social media. METHODS: We used COVID-19-related posts from the mainstream social media platform Twitter to monitor health beliefs. A total of 92,687,660 tweets corresponding to 8,967,986 unique users from January 6 to June 21, 2020, were retrieved. To quantify health beliefs, we employed the health belief model (HBM) with four core constructs: perceived susceptibility, perceived severity, perceived benefits, and perceived barriers. We utilized natural language processing and machine learning techniques to automate the process of judging the conformity of each tweet with each of the four HBM constructs. A total of 5000 tweets were manually annotated for training the machine learning architectures. RESULTS: The machine learning classifiers yielded areas under the receiver operating characteristic curves over 0.86 for the classification of all four HBM constructs. Our analyses revealed a basic reproduction number R0 of 7.62 for trends in the number of Twitter users posting health belief-related content over the study period. The fluctuations in the number of health belief-related tweets could reflect dynamics in case and death statistics, systematic interventions, and public events. Specifically, we observed that scientific events, such as scientific publications, and nonscientific events, such as politicians' speeches, were comparable in their ability to influence health belief trends on social media through a Kruskal-Wallis test (P=.78 and P=.92 for perceived benefits and perceived barriers, respectively). CONCLUSIONS: As an analogy of the classic epidemiology model where an infection is considered to be spreading in a population with an R0 greater than 1, we found that the number of users tweeting about COVID-19 health beliefs was amplifying in an epidemic manner and could partially intensify the infodemic. It is "unhealthy" that both scientific and nonscientific events constitute no disparity in impacting the health belief trends on Twitter, since nonscientific events, such as politicians' speeches, might not be endorsed by substantial evidence and could sometimes be misleading.

Learning multimorbidity patterns from electronic health records using Non-negative Matrix Factorisation.

Multimorbidity, or the presence of several medical conditions in the same individual, has been increasing in the population - both in absolute and relative terms. Nevertheless, multimorbidity remains poorly understood, and the evidence from existing research to describe its burden, determinants and consequences has been limited. Previous studies attempting to understand multimorbidity patterns are often cross-sectional and do not explicitly account for multimorbidity patterns' evolution over time; some of them are based on small datasets and/or use arbitrary and narrow age ranges; and those that employed advanced models, usually lack appropriate benchmarking and validations. In this study, we (1) introduce a novel approach for using Non-negative Matrix Factorisation (NMF) for temporal phenotyping (i.e., simultaneously mining disease clusters and their trajectories); (2) provide quantitative metrics for the evaluation of these clusters and trajectories; and (3) demonstrate how the temporal characteristics of the disease clusters that result from our model can help mine multimorbidity networks and generate new hypotheses for the emergence of various multimorbidity patterns over time. We trained and evaluated our models on one of the world's largest electronic health records (EHR) datasets, containing more than 7 million patients, from which over 2 million where relevant to, and hence included in this study.

Temporal and spatial characteristics of plantar pressure center trajectory for identifying early Parkinson's disease gait.

Gait analysis can be utilized as an effective method for identifying Parkinson's disease (PD) [1]. However, research methods based on the time-domain gait feature analysis are influenced by population characteristics such as individual height, age, and weight, which unfavorably affect PD diagnostic decision-making.

Investigation of the optimal cutting depth in small incision lenticule extraction based on a collagen fibril crimping constitutive model of the cornea.

To investigate the optimal cutting depth (Cap) in small incision lenticule extraction from the perspective of corneal biomechanics, a three-dimensional finite element model of the cornea was established using a stromal sub-regional material model to simulate small incision lenticule extraction. The displacement difference PΔ at the central point of the posterior corneal surface before and after lenticule extraction, as well as the von Mises stress at four points of different thicknesses in the center of the cornea, were analyzed using the finite element model considering the hyperelastic property and the difference in stiffness between the anterior and posterior of the cornea. The numerical curves of PΔ-Cap and von Mises Stress-Cap relations at different diopters show that the displacement difference PΔ has a smallest value at the same diopter. In this case, the von Mises stress at four points with different thicknesses in the center of the cornea was also minimal. Which means that the optimal cutting depth exsisting in the cornea. Moreover, PΔ-Cap curves for different depth of stromal stiffness boundaries show that the optimal cap thickness would change with the depth of the stromal stiffness boundary. These results are of guiding significance for accurately formulating small incision lenticule extraction surgery plans and contribute to the advancement of research on the biomechanical properties of the cornea.

Structural simulation and selective inhibitor discovery study for histone demethylases KDM4E/6B from a computational perspective.

The methylation and demethylation of lysine and arginine side chains are fundamental processes in gene regulation and disease development. Histone lysine methylation, controlled by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), plays a vital role in maintaining cellular homeostasis and has been implicated in diseases such as cancer and aging. This study focuses on two members of the lysine demethylase (KDM) family, KDM4E and KDM6B, which are significant in gene regulation and disease pathogenesis. KDM4E demonstrates selectivity for gene regulation, particularly concerning cancer, while KDM6B is implicated in inflammation and cancer. The study utilizes specific inhibitors, DA-24905 and GSK-J1, showcasing their exceptional selectivity for KDM4E and KDM6B, respectively. Employing an array of computational simulations, including sequence alignment, molecular docking, dynamics simulations, and free energy calculations, we conclude that although the binding cavities of KDM4E and KDM6B has high similarity, there are still some different crucial amino acid residues, indicating diverse binding forms between protein and ligands. Various interaction predominates when proteins are bound to different ligands, which also has significant effect on selective inhibition. These findings provide insights into potential therapeutic strategies for diseases by selectively targeting these KDM members.

A comparative study of pretrained language models for long clinical text.

OBJECTIVE: Clinical knowledge-enriched transformer models (eg, ClinicalBERT) have state-of-the-art results on clinical natural language processing (NLP) tasks. One of the core limitations of these transformer models is the substantial memory consumption due to their full self-attention mechanism, which leads to the performance degradation in long clinical texts. To overcome this, we propose to leverage long-sequence transformer models (eg, Longformer and BigBird), which extend the maximum input sequence length from 512 to 4096, to enhance the ability to model long-term dependencies in long clinical texts. MATERIALS AND METHODS: Inspired by the success of long-sequence transformer models and the fact that clinical notes are mostly long, we introduce 2 domain-enriched language models, Clinical-Longformer and Clinical-BigBird, which are pretrained on a large-scale clinical corpus. We evaluate both language models using 10 baseline tasks including named entity recognition, question answering, natural language inference, and document classification tasks. RESULTS: The results demonstrate that Clinical-Longformer and Clinical-BigBird consistently and significantly outperform ClinicalBERT and other short-sequence transformers in all 10 downstream tasks and achieve new state-of-the-art results. DISCUSSION: Our pretrained language models provide the bedrock for clinical NLP using long texts. We have made our source code available at https://github.com/luoyuanlab/Clinical-Longformer, and the pretrained models available for public download at: https://huggingface.co/yikuan8/Clinical-Longformer. CONCLUSION: This study demonstrates that clinical knowledge-enriched long-sequence transformers are able to learn long-term dependencies in long clinical text. Our methods can also inspire the development of other domain-enriched long-sequence transformers.

A comparative study of model-centric and data-centric approaches in the development of cardiovascular disease risk prediction models in the UK Biobank.

Aims: A diverse set of factors influence cardiovascular diseases (CVDs), but a systematic investigation of the interplay between these determinants and the contribution of each to CVD incidence prediction is largely missing from the literature. In this study, we leverage one of the most comprehensive biobanks worldwide, the UK Biobank, to investigate the contribution of different risk factor categories to more accurate incidence predictions in the overall population, by sex, different age groups, and ethnicity. Methods and results: The investigated categories include the history of medical events, behavioural factors, socioeconomic factors, environmental factors, and measurements. We included data from a cohort of 405 257 participants aged 37-73 years and trained various machine learning and deep learning models on different subsets of risk factors to predict CVD incidence. Each of the models was trained on the complete set of predictors and subsets where each category was excluded. The results were benchmarked against QRISK3. The findings highlight that (i) leveraging a more comprehensive medical history substantially improves model performance. Relative to QRISK3, the best performing models improved the discrimination by 3.78% and improved precision by 1.80%. (ii) Both model- and data-centric approaches are necessary to improve predictive performance. The benefits of using a comprehensive history of diseases were far more pronounced when a neural sequence model, BEHRT, was used. This highlights the importance of the temporality of medical events that existing clinical risk models fail to capture. (iii) Besides the history of diseases, socioeconomic factors and measurements had small but significant independent contributions to the predictive performance. Conclusion: These findings emphasize the need for considering broad determinants and novel modelling approaches to enhance CVD incidence prediction.

Biaxial hyperelastic and anisotropic behaviors of the corneal anterior central stroma along the preferential fibril orientations. Part II: Quantitative computational analysis of mechanical response of stromal components.

To study the hyperelastic and anisotropic behaviors of the central anterior stroma for patients with myopia, 40 corneal stromal specimens extracted after small incision lenticule extraction (SMILE) surgery were used in the biaxial extension test along two preferential fibril orientations. An improved collagen fibril crimping constitutive model with a specific physical meaning was proposed to analyze the hyperelasticity and anisotropy of the stroma. The effective elastic modulus of the two families of preferentially oriented collagen fibrils and the stiffness of the non-collagenous matrix along all three directions were compared according to the specific physical meaning of the parameters. Anisotropic behavior was found in the hyperelastic properties of the corneal anterior central stroma in the preferential fibril orientations. The stiffness of non-collagenous matrix is significantly larger in the optical axis direction than in the nasal-temporal (NT) and superior-inferior (SI) directions. Moreover, individual differences between males and females slightly impact on hyperelastic and anisotropic behaviors. The differences of these behaviors were significant in the comparison of the left and right eyes. These results have a guiding significance for the accurate design of surgical plans for refractive surgery according to a patient's condition and have a driving value for the further exploration of the biomechanical properties of the whole cornea.

Systolic blood pressure, chronic obstructive pulmonary disease and cardiovascular risk.

OBJECTIVE: In individuals with complex underlying health problems, the association between systolic blood pressure (SBP) and cardiovascular disease is less well recognised. The association between SBP and risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD) was investigated. METHODS AND ANALYSIS: In this cohort study, 39 602 individuals with a diagnosis of COPD aged 55-90 years between 1990 and 2009 were identified from validated electronic health records (EHR) in the UK. The association between SBP and risk of cardiovascular end points (composite of ischaemic heart disease, heart failure, stroke and cardiovascular death) was analysed using a deep learning approach. RESULTS: In the selected cohort (46.5% women, median age 69 years), 10 987 cardiovascular events were observed over a median follow-up period of 3.9 years. The association between SBP and risk of cardiovascular end points was found to be monotonic; the lowest SBP exposure group of <120 mm Hg presented nadir of risk. With respect to reference SBP (between 120 and 129 mm Hg), adjusted risk ratios for the primary outcome were 0.99 (95% CI 0.93 to 1.05) for SBP of <120 mm Hg, 1.02 (0.97 to 1.07) for SBP between 130 and 139 mm Hg, 1.07 (1.01 to 1.12) for SBP between 140 and 149 mm Hg, 1.11 (1.05 to 1.17) for SBP between 150 and 159 mm Hg and 1.16 (1.10 to 1.22) for SBP ≥160 mm Hg. CONCLUSION: Using deep learning for modelling EHR, we identified a monotonic association between SBP and risk of cardiovascular events in patients with COPD.

Patterns of diverse and changing sentiments towards COVID-19 vaccines: a sentiment analysis study integrating 11 million tweets and surveillance data across over 180 countries.

OBJECTIVES: Vaccines are crucial components of pandemic responses. Over 12 billion coronavirus disease 2019 (COVID-19) vaccines were administered at the time of writing. However, public perceptions of vaccines have been complex. We integrated social media and surveillance data to unravel the evolving perceptions of COVID-19 vaccines. MATERIALS AND METHODS: Applying human-in-the-loop deep learning models, we analyzed sentiments towards COVID-19 vaccines in 11 211 672 tweets of 2 203 681 users from 2020 to 2022. The diverse sentiment patterns were juxtaposed against user demographics, public health surveillance data of over 180 countries, and worldwide event timelines. A subanalysis was performed targeting the subpopulation of pregnant people. Additional feature analyses based on user-generated content suggested possible sources of vaccine hesitancy. RESULTS: Our trained deep learning model demonstrated performances comparable to educated humans, yielding an accuracy of 0.92 in sentiment analysis against our manually curated dataset. Albeit fluctuations, sentiments were found more positive over time, followed by a subsequence upswing in population-level vaccine uptake. Distinguishable patterns were revealed among subgroups stratified by demographic variables. Encouraging news or events were detected surrounding positive sentiments crests. Sentiments in pregnancy-related tweets demonstrated a lagged pattern compared with the general population, with delayed vaccine uptake trends. Feature analysis detected hesitancies stemmed from clinical trial logics, risks and complications, and urgency of scientific evidence. DISCUSSION: Integrating social media and public health surveillance data, we associated the sentiments at individual level with observed populational-level vaccination patterns. By unraveling the distinctive patterns across subpopulations, the findings provided evidence-based strategies for improving vaccine promotion during pandemics.

Stratification of diabetes in the context of comorbidities, using representation learning and topological data analysis.

Diabetes is a heterogenous, multimorbid disorder with a large variation in manifestations, trajectories, and outcomes. The aim of this study is to validate a novel machine learning method for the phenotyping of diabetes in the context of comorbidities. Data from 9967 multimorbid patients with a new diagnosis of diabetes were extracted from Clinical Practice Research Datalink. First, using BEHRT (a transformer-based deep learning architecture), the embeddings corresponding to diabetes were learned. Next, topological data analysis (TDA) was carried out to test how different areas in high-dimensional manifold correspond to different risk profiles. The following endpoints were considered when profiling risk trajectories: major adverse cardiovascular events (MACE), coronary artery disease (CAD), stroke (CVA), heart failure (HF), renal failure (RF), diabetic neuropathy, peripheral arterial disease, reduced visual acuity and all-cause mortality. Kaplan Meier curves were plotted for each derived phenotype. Finally, we tested the performance of an established risk prediction model (QRISK) by adding TDA-derived features. We identified four subgroups of patients with diabetes and divergent comorbidity patterns differing in their risk of future cardiovascular, renal, and other microvascular outcomes. Phenotype 1 (young with chronic inflammatory conditions) and phenotype 2 (young with CAD) included relatively younger patients with diabetes compared to phenotypes 3 (older with hypertension and renal disease) and 4 (older with previous CVA), and those subgroups had a higher frequency of pre-existing cardio-renal diseases. Within ten years of follow-up, 2592 patients (26%) experienced MACE, 2515 patients (25%) died, and 2020 patients (20%) suffered RF. QRISK3 model's AUC was augmented from 67.26% (CI 67.25-67.28%) to 67.67% (CI 67.66-67.69%) by adding specific TDA-derived phenotype and the distances to both extremities of the TDA graph improving its performance in the prediction of CV outcomes. We confirmed the importance of accounting for multimorbidity when risk stratifying heterogenous cohort of patients with new diagnosis of diabetes. Our unsupervised machine learning method improved the prediction of clinical outcomes.

Systolic Blood Pressure and Cardiovascular Risk in Patients With Diabetes: A Prospective Cohort Study.

BACKGROUND: Whether the association between systolic blood pressure (SBP) and risk of cardiovascular disease is monotonic or whether there is a nadir of optimal blood pressure remains controversial. We investigated the association between SBP and cardiovascular events in patients with diabetes across the full spectrum of SBP. METHODS: A cohort of 49 000 individuals with diabetes aged 50 to 90 years between 1990 and 2005 was identified from linked electronic health records in the United Kingdom. Associations between SBP and cardiovascular outcomes (ischemic heart disease, heart failure, stroke, and cardiovascular death) were analyzed using a deep learning approach. RESULTS: Over a median follow-up of 7.3 years, 16 378 cardiovascular events were observed. The relationship between SBP and cardiovascular events followed a monotonic pattern, with the group with the lowest baseline SBP of <120 mm Hg exhibiting the lowest risk of cardiovascular events. In comparison to the reference group with the lowest SBP (<120 mm Hg), the adjusted risk ratio for cardiovascular disease was 1.03 (95% CI, 0.97-1.10) for SBP between 120 and 129 mm Hg, 1.05 (0.99-1.11) for SBP between 130 and 139 mm Hg, 1.08 (1.01-1.15) for SBP between 140 and 149 mm Hg, 1.12 (1.03-1.20) for SBP between 150 and 159 mm Hg, and 1.19 (1.09-1.28) for SBP ≥160 mm Hg. CONCLUSIONS: Using deep learning modeling, we found a monotonic relationship between SBP and risk of cardiovascular outcomes in patients with diabetes, without evidence of a J-shaped relationship.

Hi-BEHRT: Hierarchical Transformer-Based Model for Accurate Prediction of Clinical Events Using Multimodal Longitudinal Electronic Health Records.

Electronic health records (EHR) represent a holistic overview of patients' trajectories. Their increasing availability has fueled new hopes to leverage them and develop accurate risk prediction models for a wide range of diseases. Given the complex interrelationships of medical records and patient outcomes, deep learning models have shown clear merits in achieving this goal. However, a key limitation of current study remains their capacity in processing long sequences, and long sequence modelling and its application in the context of healthcare and EHR remains unexplored. Capturing the whole history of medical encounters is expected to lead to more accurate predictions, but the inclusion of records collected for decades and from multiple resources can inevitably exceed the receptive field of the most existing deep learning architectures. This can result in missing crucial, long-term dependencies. To address this gap, we present Hi-BEHRT, a hierarchical Transformer-based model that can significantly expand the receptive field of Transformers and extract associations from much longer sequences. Using a multimodal large-scale linked longitudinal EHR, the Hi-BEHRT exceeds the state-of-the-art deep learning models 1% to 5% for area under the receiver operating characteristic (AUROC) curve and 1% to 8% for area under the precision recall (AUPRC) curve on average, and 2% to 8% (AUROC) and 2% to 11% (AUPRC) for patients with long medical history for 5-year heart failure, diabetes, chronic kidney disease, and stroke risk prediction. Additionally, because pretraining for hierarchical Transformer is not well-established, we provide an effective end-to-end contrastive pre-training strategy for Hi-BEHRT using EHR, improving its transferability on predicting clinical events with relatively small training dataset.

Evaluation of the portability of computable phenotypes with natural language processing in the eMERGE network.

The electronic Medical Records and Genomics (eMERGE) Network assessed the feasibility of deploying portable phenotype rule-based algorithms with natural language processing (NLP) components added to improve performance of existing algorithms using electronic health records (EHRs). Based on scientific merit and predicted difficulty, eMERGE selected six existing phenotypes to enhance with NLP. We assessed performance, portability, and ease of use. We summarized lessons learned by: (1) challenges; (2) best practices to address challenges based on existing evidence and/or eMERGE experience; and (3) opportunities for future research. Adding NLP resulted in improved, or the same, precision and/or recall for all but one algorithm. Portability, phenotyping workflow/process, and technology were major themes. With NLP, development and validation took longer. Besides portability of NLP technology and algorithm replicability, factors to ensure success include privacy protection, technical infrastructure setup, intellectual property agreement, and efficient communication. Workflow improvements can improve communication and reduce implementation time. NLP performance varied mainly due to clinical document heterogeneity; therefore, we suggest using semi-structured notes, comprehensive documentation, and customization options. NLP portability is possible with improved phenotype algorithm performance, but careful planning and architecture of the algorithms is essential to support local customizations.