Applying Machine Learning to Blood Count Data Predicts Sepsis with ICU Admission.

BACKGROUND: Timely diagnosis is crucial for sepsis treatment. Current machine learning (ML) models suffer from high complexity and limited applicability. We therefore created an ML model using only complete blood count (CBC) diagnostics. METHODS: We collected non-intensive care unit (non-ICU) data from a German tertiary care centre (January 2014 to December 2021). Using patient age, sex, and CBC parameters (haemoglobin, platelets, mean corpuscular volume, white and red blood cells), we trained a boosted random forest, which predicts sepsis with ICU admission. Two external validations were conducted using data from another German tertiary care centre and the Medical Information Mart for Intensive Care IV database (MIMIC-IV). Using the subset of laboratory orders also including procalcitonin (PCT), an analogous model was trained with PCT as an additional feature. RESULTS: After exclusion, 1 381 358 laboratory requests (2016 from sepsis cases) were available. The CBC model shows an area under the receiver operating characteristic (AUROC) of 0.872 (95% CI, 0.857-0.887). External validations show AUROCs of 0.805 (95% CI, 0.787-0.824) for University Medicine Greifswald and 0.845 (95% CI, 0.837-0.852) for MIMIC-IV. The model including PCT revealed a significantly higher AUROC (0.857; 95% CI, 0.836-0.877) than PCT alone (0.790; 95% CI, 0.759-0.821; P < 0.001). CONCLUSIONS: Our results demonstrate that routine CBC results could significantly improve diagnosis of sepsis when combined with ML. The CBC model can facilitate early sepsis prediction in non-ICU patients with high robustness in external validations. Its implementation in clinical decision support systems has strong potential to provide an essential time advantage and increase patient safety.

Evidence-based cutoffs for total and adjusted calcium: a major factor in detecting severe hypo- and hypercalcemia.

OBJECTIVES: Severe hypo- and hypercalcemia are common and urgent treatment is recommended. Free calcium (fCa) is the gold standard but needs blood gas tests with challenging preanalytics. Total calcium (tCa) and calculated adjusted calcium (aCa) are readily available, but their interpretation is hampered by identical tCa and aCa cutoffs, laborious local aCa calculation and difficult comparability of calcium biomarkers. METHODS: Laboratory results from University Medicine Leipzig were evaluated over a five-year period (236,274 patients). A local aCa equation was derived by linear least squares regression, the agreement between fCa, tCa and aCa assessed with Cohen's κ and decision thresholds derived by this indirect method. RESULTS: The local aCa equation was created from data of 9,756 patients, each with one paired measurement of tCa, fCa and albumin. Derived aCa cutoffs (1.95/3.15 mmol/L) differ markedly from derived tCa cutoffs (1.6/2.9 mmol/L) and severe hypo- and hypercalcemia can be more accurately assessed by aCa (κ=0.489, 0.812) than by tCa (κ=0.445, 0.744). Comparing our approach to standard care (tCa, literature cutoff), a total 3,250 of 3,680 (88.3 %) misclassified measurements were correctly classified when using aCa with evidence-based cutoffs. CONCLUSIONS: Optimized cutoffs for aCa and tCa hold great potential for improved patient care. Locally derived aCa equations differ mostly in the chosen mean normal calcium and provide minimal overall improvement, but entail a close examination of the used cutoffs before application.

Development, Design and Utilization of a CDSS for Refeeding Syndrome in Real Life Inpatient Care-A Feasibility Study.

BACKGROUND: The refeeding syndrome (RFS) is an oftentimes-unrecognized complication of reintroducing nutrition in malnourished patients that can lead to fatal cardiovascular failure. We hypothesized that a clinical decision support system (CDSS) can improve RFS recognition and management. METHODS: We developed an algorithm from current diagnostic criteria for RFS detection, tested the algorithm on a retrospective dataset and combined the final algorithm with therapy and referral recommendations in a knowledge-based CDSS. The CDSS integration into clinical practice was prospectively investigated for six months. RESULTS: The utilization of the RFS-CDSS lead to RFS diagnosis in 13 out of 21 detected cases (62%). It improved patient-related care and documentation, e.g., RFS-specific coding (E87.7), increased from once coded in 30 month in the retrospective cohort to four times in six months in the prospective cohort and doubled the rate of nutrition referrals in true positive patients (retrospective referrals in true positive patients 33% vs. prospective referrals in true positive patients 71%). CONCLUSION: CDSS-facilitated RFS diagnosis is possible and improves RFS recognition. This effect and its impact on patient-related outcomes needs to be further investigated in a large randomized-controlled trial.

Laboratory Diagnostic of Acute Kidney Injury and Its Progression: Risk of Underdiagnosis in Female and Elderly Patients.

Acute kidney injury (AKI) is a common disease, with high morbidity and mortality rates. In this study, we investigated the potential influence of sex and age on laboratory diagnostics and outcomes. It is known that serum creatinine (SCr) has limitations as a laboratory diagnostic parameter for AKI due to its dependence on muscle mass, which may lead to an incorrect or delayed diagnosis for certain patient groups, such as women and the elderly. Overall, 7592 cases with AKI, hospitalized at the University of Leipzig Medical Center (ULMC) between 1st January 2017 and 31st December 2019, were retrospectively analyzed. The diagnosis and staging of AKI were performed according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, based on the level and dynamics of SCr. The impact of sex and age was analyzed by the recalculation of a female to male and an old to young SCr using the CKD-EPI equation. In our study cohort progressive AKI occurred in 19.2% of all cases (n = 1458). Female cases with AKI were underrepresented (40.4%), with a significantly lower first (-3.5 mL/min) and last eGFR (-2.7 mL/min) (p < 0.001). The highest incidence proportion of AKI was found in the [61-81) age group in female (49.5%) and male (52.7%) cases. Females with progressive AKI were underrepresented (p = 0.04). By defining and staging AKI on the basis of relative and absolute changes in the SCr level, it is more difficult for patients with low muscle mass and, thus, a lower baseline SCr to be diagnosed by an absolute SCr increase. AKIN1 and AKIN3 can be diagnosed by a relative or absolute change in SCr. In females, both stages were less frequently detected by an absolute criterion alone (AKIN1 ♀ 20.2%, ♂ 29.5%, p < 0.001; AKIN3 ♀ 13.4%, ♂ 15.2%, p < 0.001). A recalculated SCr for females (as males) and males (as young males) displayed the expected increase in AKI occurrence and severity with age and, in general, in females. Our study illustrates how SCr, as the sole parameter for the diagnosis and staging of AKI, bears the risk of underdiagnosis of patient groups with low muscle mass, such as women and the elderly. A sex- and age-adapted approach might offer advantages.

Challenge in hyponatremic patients - the potential of a laboratory-based decision support system for hyponatremia to improve patient's safety.

OBJECTIVES: Hyponatremia is the most frequent electrolyte disorder in hospitalized patients with increased mortality and morbidity. In this study, we evaluated the follow-up diagnostic, the risk of inadequate fast correction and the outcome of patients with profound hyponatremia (pHN), defined as a blood sodium concentration below 120 mmol/L. The aim was to identify a promising approach for a laboratory-based clinical decision support system (CDSS). METHODS: This retrospective study included 378,980 blood sodium measurements of 83,315 cases at a German tertiary care hospital. Hospitalized cases with pHN (n=211) were categorized into two groups by the time needed for a follow-up measurement to be performed (time to control, TTC) as either <12 h (group 1: "TTC≤12 h", n=118 cases) or >12 h (group 2: "TTC>12 h", n=93 cases). Length of hospital stay, sodium level at discharge, ward transfers, correction of hyponatremia, and risk of osmotic demyelination syndrome (ODS) due to inadequate fast correction were evaluated with regard to the TTC of sodium blood concentration. RESULTS: pHN was detected in 1,050 measurements (0.3%) in 211 cases. Cases, in which follow-up diagnostics took longer (TTC>12 h), achieved a significantly lower sodium correction during their hospitalization (11.2 vs. 16.7 mmol/L, p<0.001), were discharged more frequently in hyponatremic states (<135 mmol/L; 58 (62.4%) vs. 43 (36.4%), p<0.001) and at lower sodium blood levels (131.2 vs. 135.0 mmol/L, p<0.001). Furthermore, for these patients there was a trend toward an increased length of hospital stay (13.1 vs. 8.5 days, p=0.089), as well as an increased risk of inadequate fast correction (p<0.001). CONCLUSIONS: Our study shows that less frequent follow-up sodium measurements in pHN are associated with worse outcomes. Patients with a prolonged TTC are at risk of insufficient correction of hyponatremia, reduced sodium values at discharge, and possible overcorrection. Our results suggest that a CDSS that alerts treating physicians when a control time of >12 h is exceeded could improve patient care in the long term. We are initiating a prospective study to investigate the benefits of our self-invented CDSS (www.ampel.care) for patients with pHN.

Revisited Upper Reference Limits for Highly Sensitive Cardiac Troponin T in Relation to Age, Sex, and Renal Function.

(1) Background: Highly sensitive cardiac troponin T (hs-cTnT) plays an essential role in the diagnosis of myocardial injury. The upper reference limit of the respective assay is generally applied, irrespective of age, renal function, or sex. We aimed to identify age-adjusted and sex-adjusted upper reference limits in relation to renal function in a large population-based cohort without cardiac diseases. (2) Methods: We included 5428 subjects of the population-based LIFE-Adult cohort, free of diagnosed cardiac diseases. Sex-adjusted and age-adjusted 99th percentiles for hs-cTnT in subjects with preserved renal function were obtained. (3) Results: The hs-cTnT values were higher in men of all age groups. In both sexes, an increasing age positively correlated with higher hs-cTnT values. Hs-cTnT weakly correlated with serum creatinine. The three-dimensional analysis of age, creatinine, and hs-cTnT showed no relevant additional effect of creatinine on hs-cTnT. In men aged above 60 and women above 70, the calculated 99th percentiles clearly exceeded the commonly applied thresholds. (4) Conclusion: Age and sex have a major impact on the serum concentration of hs-cTnT, while renal function does not. We propose to consider age-adjusted and sex-adjusted reference values.

A Combined Clinical and Serum Biomarker-Based Approach May Allow Early Differentiation Between Patients With Minor Stroke and Transient Ischemic Attack as Well as Mid-term Prognostication.

Background: Early differentiation between transient ischemic attack (TIA) and minor ischemic stroke (MIS) impacts on the patient's individual diagnostic work-up and treatment. Furthermore, estimations regarding persisting impairments after MIS are essential to guide rehabilitation programs. This study evaluated a combined clinical- and serum biomarker-based approach for the differentiation between TIA and MIS as well as the mid-term prognostication of the functional outcome, which is applicable within the first 24 h after symptom onset. Methods: Prospectively collected data were used for a retrospective analysis including the neurological deficit at admission (National Institutes of Health Stroke Scale, NIHSS) and the following serum biomarkers covering different pathophysiological aspects of stroke: Coagulation (fibrinogen, antithrombin), inflammation (C reactive protein), neuronal damage in the cellular [neuron specific enolase], and the extracellular compartment [matrix metalloproteinase-9, hyaluronic acid]. Further, cerebral magnetic resonance imaging was performed at baseline and day 7, while functional outcome was evaluated with the modified Rankin Scale (mRS) after 3, 6, and 12 months. Results: Based on data from 96 patients (age 64 ± 14 years), 23 TIA patients (NIHSS 0.6 ± 1.1) were compared with 73 MIS patients (NIHSS 2.4 ± 2.0). In a binary logistic regression analysis, the combination of NIHSS and serum biomarkers differentiated MIS from TIA with a sensitivity of 91.8% and a specificity of 60.9% [area under the curve (AUC) 0.84]. In patients with NIHSS 0 at admission, this panel resulted in a still acceptable sensitivity of 81.3% (specificity 71.4%, AUC 0.69) for the differentiation between MIS (n = 16) and TIA (n = 14). By adding age, remarkable sensitivities of 98.4, 100, and 98.2% for the prediction of an excellent outcome (mRS 0 or 1) were achieved with respect to time points investigated within the 1-year follow-up. However, the specificity was moderate and decreased over time (83.3, 70, 58.3%; AUC 0.96, 0.92, 0.91). Conclusion: This pilot study provides evidence that the NIHSS combined with selected serum biomarkers covering pathophysiological aspects of stroke may represent a useful tool to differentiate between MIS and TIA within 24 h after symptom onset. Further, this approach may accurately predict the mid-term outcome in minor stroke patients, which might help to allocate rehabilitative resources.

Acute kidney injury and its progression in hospitalized patients-Results from a retrospective multicentre cohort study with a digital decision support system.

In this retrospective multicentric cohort study, we evaluate the potential benefits of a clinical decision support system (CDSS) for the automated detection of Acute kidney injury (AKI). A total of 80,389 cases, hospitalized from 2017 to 2019 at a tertiary care hospital (University of Leipzig Medical Center (ULMC)) and two primary care hospitals (Muldentalkliniken (MTL)) in Germany, were enrolled. AKI was defined and staged according to the Kidney disease: improving global outcomes (KDIGO) guidelines. Clinical and laboratory data was automatically collected from electronic patient records using the frameworks of the CDSS. In our cohort, we found an overall AKI incidence proportion of 12.1%. We identified 6,393/1,703/1,604 cases as AKI stage 1/2/3 (8.0%/2.1%/2.0%, respectively). Administrative coding with N17 (ICD-10-GM) was missing in 55.8% of all AKI cases with the potential for additional diagnosis related groups (DRG) reimbursement of 1,204,200 € in our study. AKI was associated with higher hospital mortality, increased length of hospitalisation and more frequent need of renal replacement therapy. A total of 19.1% of AKI cases (n = 1,848) showed progression to higher AKI stages (progressive AKI) during hospitalization. These cases presented with considerably longer hospitalization, higher rates of renal replacement therapy and increased mortality (p<0.001, respectively). Furthermore, progressive AKI was significantly associated with sepsis, shock, liver cirrhosis, myocardial infarction, and cardiac insufficiency. AKI, and especially its progression during hospitalization, is strongly associated with adverse outcomes. Our automated CDSS enables timely detection and bears potential to improve AKI outcomes, notably in cases of progressive AKI.

The Clinical Decision Support System AMPEL for Laboratory Diagnostics: Implementation and Technical Evaluation.

BACKGROUND: Laboratory results are of central importance for clinical decision making. The time span between availability and review of results by clinicians is crucial to patient care. Clinical decision support systems (CDSS) are computational tools that can identify critical values automatically and help decrease treatment delay. OBJECTIVE: With this work, we aimed to implement and evaluate a CDSS that supports health care professionals and improves patient safety. In addition to our experiences, we also describe its main components in a general manner to make it applicable to a wide range of medical institutions and to empower colleagues to implement a similar system in their facilities. METHODS: Technical requirements must be taken into account before implementing a CDSS that performs laboratory diagnostics (labCDSS). These can be planned within the functional components of a reactive software agent, a computational framework for such a CDSS. RESULTS: We present AMPEL (Analysis and Reporting System for the Improvement of Patient Safety through Real-Time Integration of Laboratory Findings), a labCDSS that notifies health care professionals if a life-threatening medical condition is detected. We developed and implemented AMPEL at a university hospital and regional hospitals in Germany (University of Leipzig Medical Center and the Muldental Clinics in Grimma and Wurzen). It currently runs 5 different algorithms in parallel: hypokalemia, hypercalcemia, hyponatremia, hyperlactatemia, and acute kidney injury. CONCLUSIONS: AMPEL enables continuous surveillance of patients. The system is constantly being evaluated and extended and has the capacity for many more algorithms. We hope to encourage colleagues from other institutions to design and implement similar CDSS using the theory, specifications, and experiences described in this work.

Predictors for blood loss and transfusion frequency to guide blood saving programs in primary knee- and hip-arthroplasty.

Endoprosthetic surgery can lead to relevant blood loss resulting in red blood cell (RBC) transfusions. This study aimed to identify risk factors for blood loss and RBC transfusion that enable the prediction of an individualized transfusion probability to guide preoperative RBC provision and blood saving programs. A retrospective analysis of patients who underwent primary hip or knee arthroplasty was performed. Risk factors for blood loss and transfusions were identified and transfusion probabilities computed. The number needed to treat (NNT) of a potential correction of preoperative anemia with iron substitution for the prevention of RBC transfusion was calculated. A total of 308 patients were included, of whom 12 (3.9%) received RBC transfusions. Factors influencing the maximum hemoglobin drop were the use of drain, tranexamic acid, duration of surgery, anticoagulation, BMI, ASA status and mechanical heart valves. In multivariate analysis, the use of a drain, low preoperative Hb and mechanical heart valves were predictors for RBC transfusions. The transfusion probability of patients with a hemoglobin of 9.0-10.0 g/dL, 10.0-11.0 g/dL, 11.0-12.0 g/dL and 12.0-13.0 g/dL was 100%, 33.3%, 10% and 5.6%, and the NNT 1.5, 4.3, 22.7 and 17.3, while it was 100%, 50%, 25% and 14.3% with a NNT of 2.0, 4.0, 9.3 and 7.0 in patients with a drain, respectively. Preoperative anemia and the insertion of drains are more predictive for RBC transfusions than the use of tranexamic acid. Based on this, a personalized transfusion probability can be computed, that may help to identify patients who could benefit from blood saving programs.

Genetic variants in AKR1B10 associate with human eating behavior.

BACKGROUND: The human Aldoketoreductase 1B10 gene (AKR1B10) encodes one of the enzymes belonging to the family of aldoketoreductases and may be involved in detoxification of nutrients during digestion. Further, AKR1B10 mRNA (messenger ribonucleic acid) expression was diminished in brain regions potentially involved in the regulation of eating behavior in rats which are more sensitive to cocaine and alcohol. We hypothesized that the human AKR1B10 gene may also play a role in the regulation of human eating behavior. RESULTS: We investigated the effects of 5 genetic variants of AKR1B10 on human eating behavior among 548 subjects from a German self-contained population, the Sorbs, and in 350 subjects from another independent German cohort. Among the Sorbs, we observed nominal associations with disinhibition at the 5' untranslated region (5' UTR) variant rs10232478 and the intragenic variants rs1834150 and rs782881 (all P ≤ 0.05). Further, we detected a relationship of rs1834150 and rs782881 with waist, smoking consumption (rs782881) and coffee consumption (rs1834150) (all P ≤ 0.05). Albeit non-significant, replication analyses revealed similar effect directions for disinhibition at rs1834150 (combined P = 0.0096). Moreover, in the replication cohort we found rs1834150 related to increased restraint scores with a similar direction as in the Sorbs (combined P = 0.0072). CONCLUSION: Our data suggest that genetic variants in the AKR1B10 locus may influence human eating behavior.

Body weight status, eating behavior, sensitivity to reward/punishment, and gender: relationships and interdependencies.

Behavioral and personality characteristics are factors that may jointly regulate body weight. This study explored the relationship between body mass index (BMI) and self-reported behavioral and personality measures. These measures included eating behavior (based on the Three-Factor Eating Questionnaire; Stunkard and Messick, 1985), sensitivity to reward and punishment (based on the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scales) (Carver and White, 1994) and self-reported impulsivity (based on the Barratt Impulsiveness Scale-11; Patton et al., 1995). We found an inverted U-shaped relationship between restrained eating and BMI. This relationship was moderated by the level of disinhibited eating. Independent of eating behavior, BIS and BAS responsiveness were associated with BMI in a gender-specific manner with negative relationships for men and positive relationships for women. Together, eating behavior and BIS/BAS responsiveness accounted for a substantial proportion of BMI variance (men: ∼25%, women: ∼32%). A direct relationship between self-reported impulsivity and BMI was not observed. In summary, our results demonstrate a system of linear and non-linear relationships between the investigated factors and BMI. Moreover, body weight status was not only associated with eating behavior (cognitive restraint and disinhibition), but also with personality factors not inherently related to an eating context (BIS/BAS). Importantly, these relationships differ between men and women.