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1. Sepsis subphenotyping based on organ dysfunction trajectory

   https://doi.org/10.1186/s13054-022-04071-4  

   Xu, Zhenxing; Mao, Chengsheng; Su, Chang; Zhang, Hao; Siempos, Ilias; Torres, Lisa K.; Pan, Di; Luo, Yuan; Schenck, Edward J.; Wang, Fei (December 2022, Critical Care)

   Abstract Background Sepsis is a heterogeneous syndrome, and the identification of clinical subphenotypes is essential. Although organ dysfunction is a defining element of sepsis, subphenotypes of differential trajectory are not well studied. We sought to identify distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis. Methods We created 72-h SOFA score trajectories in patients with sepsis from four diverse intensive care unit (ICU) cohorts. We then used dynamic time warping (DTW) to compute heterogeneous SOFA trajectory similarities and hierarchical agglomerative clustering (HAC) to identify trajectory-based subphenotypes. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership at 6 and 24 h after being admitted to the ICU. The model was tested on three validation cohorts. Sensitivity analyses were performed with alternative clustering methodologies. Results A total of 4678, 3665, 12,282, and 4804 unique sepsis patients were included in development and three validation cohorts, respectively. Four subphenotypes were identified in the development cohort: Rapidly Worsening ( n  = 612, 13.1%), Delayed Worsening ( n  = 960, 20.5%), Rapidly Improving ( n  = 1932, 41.3%), and Delayed Improving ( n  = 1174, 25.1%). Baseline characteristics, including the pattern of organ dysfunction, varied between subphenotypes. Rapidly Worsening was defined by a higher comorbidity burden, acidosis, and visceral organ dysfunction. Rapidly Improving was defined by vasopressor use without acidosis. Outcomes differed across the subphenotypes, Rapidly Worsening had the highest in-hospital mortality (28.3%, P -value < 0.001), despite a lower SOFA (mean: 4.5) at ICU admission compared to Rapidly Improving (mortality:5.5%, mean SOFA: 5.5). An overall prediction accuracy of 0.78 (95% CI, [0.77, 0.8]) was obtained at 6 h after ICU admission, which increased to 0.87 (95% CI, [0.86, 0.88]) at 24 h. Similar subphenotypes were replicated in three validation cohorts. The majority of patients with sepsis have an improving phenotype with a lower mortality risk; however, they make up over 20% of all deaths due to their larger numbers. Conclusions Four novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Identifying trajectory-based subphenotypes has immediate implications for the powering and predictive enrichment of clinical trials. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets and identify more precise populations and endpoints for clinical trials. 

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2. DeepSOFA: A Continuous Acuity Score for Critically Ill Patients using Clinically Interpretable Deep Learning

   https://doi.org/10.1038/s41598-019-38491-0  

   Shickel, Benjamin; Loftus, Tyler J.; Adhikari, Lasith; Ozrazgat-Baslanti, Tezcan; Bihorac, Azra; Rashidi, Parisa (February 2019, Scientific Reports)

   Abstract Traditional methods for assessing illness severity and predicting in-hospital mortality among critically ill patients require time-consuming, error-prone calculations using static variable thresholds. These methods do not capitalize on the emerging availability of streaming electronic health record data or capture time-sensitive individual physiological patterns, a critical task in the intensive care unit. We propose a novel acuity score framework (DeepSOFA) that leverages temporal measurements and interpretable deep learning models to assess illness severity at any point during an ICU stay. We compare DeepSOFA with SOFA (Sequential Organ Failure Assessment) baseline models using the same model inputs and find that at any point during an ICU admission, DeepSOFA yields significantly more accurate predictions of in-hospital mortality. A DeepSOFA model developed in a public database and validated in a single institutional cohort had a mean AUC for the entire ICU stay of 0.90 (95% CI 0.90–0.91) compared with baseline SOFA models with mean AUC 0.79 (95% CI 0.79–0.80) and 0.85 (95% CI 0.85–0.86). Deep models are well-suited to identify ICU patients in need of life-saving interventions prior to the occurrence of an unexpected adverse event and inform shared decision-making processes among patients, providers, and families regarding goals of care and optimal resource utilization. 

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3. Physiologic signatures within six hours of hospitalization identify acute illness phenotypes

   https://doi.org/10.1371/journal.pdig.0000110  

   Ren, Yuanfang; Loftus, Tyler J.; Li, Yanjun; Guan, Ziyuan; Ruppert, Matthew M.; Datta, Shounak; Upchurch, Gilbert R.; Tighe, Patrick J.; Rashidi, Parisa; Shickel, Benjamin; et al (October 2022, PLOS Digital Health)

   Keim-Malpass, Jessica (Ed.)

   During the early stages of hospital admission, clinicians use limited information to make decisions as patient acuity evolves. We hypothesized that clustering analysis of vital signs measured within six hours of hospital admission would reveal distinct patient phenotypes with unique pathophysiological signatures and clinical outcomes. We created a longitudinal electronic health record dataset for 75,762 adult patient admissions to a tertiary care center in 2014–2016 lasting six hours or longer. Physiotypes were derived via unsupervised machine learning in a training cohort of 41,502 patients applying consensus k -means clustering to six vital signs measured within six hours of admission. Reproducibility and correlation with clinical biomarkers and outcomes were assessed in validation cohort of 17,415 patients and testing cohort of 16,845 patients. Training, validation, and testing cohorts had similar age (54–55 years) and sex (55% female), distributions. There were four distinct clusters. Physiotype A had physiologic signals consistent with early vasoplegia, hypothermia, and low-grade inflammation and favorable short-and long-term clinical outcomes despite early, severe illness. Physiotype B exhibited early tachycardia, tachypnea, and hypoxemia followed by the highest incidence of prolonged respiratory insufficiency, sepsis, acute kidney injury, and short- and long-term mortality. Physiotype C had minimal early physiological derangement and favorable clinical outcomes. Physiotype D had the greatest prevalence of chronic cardiovascular and kidney disease, presented with severely elevated blood pressure, and had good short-term outcomes but suffered increased 3-year mortality. Comparing sequential organ failure assessment (SOFA) scores across physiotypes demonstrated that clustering did not simply recapitulate previously established acuity assessments. In a heterogeneous cohort of hospitalized patients, unsupervised machine learning techniques applied to routine, early vital sign data identified physiotypes with unique disease categories and distinct clinical outcomes. This approach has the potential to augment understanding of pathophysiology by distilling thousands of disease states into a few physiological signatures. 

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4. Comparison of time series clustering methods for identifying novel subphenotypes of patients with infection

   https://doi.org/10.1093/jamia/ocad063  

   Bhavani, Sivasubramanium V; Xiong, Li; Pius, Abish; Semler, Matthew; Qian, Edward T; Verhoef, Philip A; Robichaux, Chad; Coopersmith, Craig M; Churpek, Matthew M (April 2023, Journal of the American Medical Informatics Association)

   Abstract Objective Severe infection can lead to organ dysfunction and sepsis. Identifying subphenotypes of infected patients is essential for personalized management. It is unknown how different time series clustering algorithms compare in identifying these subphenotypes. Materials and Methods Patients with suspected infection admitted between 2014 and 2019 to 4 hospitals in Emory healthcare were included, split into separate training and validation cohorts. Dynamic time warping (DTW) was applied to vital signs from the first 8 h of hospitalization, and hierarchical clustering (DTW-HC) and partition around medoids (DTW-PAM) were used to cluster patients into subphenotypes. DTW-HC, DTW-PAM, and a previously published group-based trajectory model (GBTM) were evaluated for agreement in subphenotype clusters, trajectory patterns, and subphenotype associations with clinical outcomes and treatment responses. Results There were 12 473 patients in training and 8256 patients in validation cohorts. DTW-HC, DTW-PAM, and GBTM models resulted in 4 consistent vitals trajectory patterns with significant agreement in clustering (71–80% agreement, P < .001): group A was hyperthermic, tachycardic, tachypneic, and hypotensive. Group B was hyperthermic, tachycardic, tachypneic, and hypertensive. Groups C and D had lower temperatures, heart rates, and respiratory rates, with group C normotensive and group D hypotensive. Group A had higher odds ratio of 30-day inpatient mortality (P < .01) and group D had significant mortality benefit from balanced crystalloids compared to saline (P < .01) in all 3 models. Discussion DTW- and GBTM-based clustering algorithms applied to vital signs in infected patients identified consistent subphenotypes with distinct clinical outcomes and treatment responses. Conclusion Time series clustering with distinct computational approaches demonstrate similar performance and significant agreement in the resulting subphenotypes. 

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5. Characterizing Macrophages Diversity in COVID-19 Patients Using Deep Learning

   https://doi.org/10.3390/genes13122264  

   Flores, Mario A.; Paniagua, Karla; Huang, Wenjian; Ramirez, Ricardo; Falcon, Leonardo; Liu, Andy; Chen, Yidong; Huang, Yufei; Jin, Yufang (December 2022, Genes)

   The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for coronavirus disease 2019 (COVID-19), has affected the lives of billions and killed millions of infected people. This virus has been demonstrated to have different outcomes among individuals, with some of them presenting a mild infection, while others present severe symptoms or even death. The identification of the molecular states related to the severity of a COVID-19 infection has become of the utmost importance to understanding the differences in critical immune response. In this study, we computationally processed a set of publicly available single-cell RNA-Seq (scRNA-Seq) data of 12 Bronchoalveolar Lavage Fluid (BALF) samples diagnosed as having a mild, severe, or no infection, and generated a high-quality dataset that consists of 63,734 cells, each with 23,916 genes. We extended the cell-type and sub-type composition identification and our analysis showed significant differences in cell-type composition in mild and severe groups compared to the normal. Importantly, inflammatory responses were dramatically elevated in the severe group, which was evidenced by the significant increase in macrophages, from 10.56% in the normal group to 20.97% in the mild group and 34.15% in the severe group. As an indicator of immune defense, populations of T cells accounted for 24.76% in the mild group and decreased to 7.35% in the severe group. To verify these findings, we developed several artificial neural networks (ANNs) and graph convolutional neural network (GCNN) models. We showed that the GCNN models reach a prediction accuracy of the infection of 91.16% using data from subtypes of macrophages. Overall, our study indicates significant differences in the gene expression profiles of inflammatory response and immune cells of severely infected patients. 

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