Informative missingness: What can we learn from patterns in missing laboratory data in the electronic health record?

BACKGROUND: In electronic health records, patterns of missing laboratory test results could capture patients' course of disease as well as ​​reflect clinician's concerns or worries for possible conditions. These patterns are often understudied and overlooked. This study aims to identify informative patterns of missingness among laboratory data collected across 15 healthcare system sites in three countries for COVID-19 inpatients. METHODS: We collected and analyzed demographic, diagnosis, and laboratory data for 69,939 patients with positive COVID-19 PCR tests across three countries from 1 January 2020 through 30 September 2021. We analyzed missing laboratory measurements across sites, missingness stratification by demographic variables, temporal trends of missingness, correlations between labs based on missingness indicators over time, and clustering of groups of labs based on their missingness/ordering pattern. RESULTS: With these analyses, we identified mapping issues faced in seven out of 15 sites. We also identified nuances in data collection and variable definition for the various sites. Temporal trend analyses may support the use of laboratory test result missingness patterns in identifying severe COVID-19 patients. Lastly, using missingness patterns, we determined relationships between various labs that reflect clinical behaviors. CONCLUSION: In this work, we use computational approaches to relate missingness patterns to hospital treatment capacity and highlight the heterogeneity of looking at COVID-19 over time and at multiple sites, where there might be different phases, policies, etc. Changes in missingness could suggest a change in a patient's condition, and patterns of missingness among laboratory measurements could potentially identify clinical outcomes. This allows sites to consider missing data as informative to analyses and help researchers identify which sites are better poised to study particular questions.

Development of a colorimetric α-ketoglutarate detection assay for prolyl hydroxylase domain (PHD) proteins.

Since the discovery of the prolyl hydroxylases domain (PHD) proteins and their canonical hypoxia-inducible factor (HIF) substrate two decades ago, a number of in vitro hydroxylation (IVH) assays for PHD activity have been developed to measure the PHD-HIF interaction. However, most of these assays either require complex proteomics mass spectrometry methods that rely on the specific PHD-HIF interaction or require the handling of radioactive material, as seen in the most commonly used assay measuring [14C]O2 release from labeled [14C]α-ketoglutarate. Here, we report an alternative rapid, cost-effective assay in which the consumption of α-ketoglutarate is monitored by its derivatization with 2,4-dinitrophenylhydrazine (2,4-DNPH) followed by treatment with concentrated base. We extensively optimized this 2,4-DNPH α-ketoglutarate assay to maximize the signal-to-noise ratio and demonstrated that it is robust enough to obtain kinetic parameters of the well-characterized PHD2 isoform comparable with those in published literature. We further showed that it is also sensitive enough to detect and measure the IC50 values of pan-PHD inhibitors and several PHD2 inhibitors in clinical trials for chronic kidney disease (CKD)-induced anemia. Given the efficiency of this assay coupled with its multiwell format, the 2,4-DNPH α-KG assay may be adaptable to explore non-HIF substrates of PHDs and potentially to high-throughput assays.

Distinguishing Admissions Specifically for COVID-19 From Incidental SARS-CoV-2 Admissions: National Retrospective Electronic Health Record Study.

BACKGROUND: Admissions are generally classified as COVID-19 hospitalizations if the patient has a positive SARS-CoV-2 polymerase chain reaction (PCR) test. However, because 35% of SARS-CoV-2 infections are asymptomatic, patients admitted for unrelated indications with an incidentally positive test could be misclassified as a COVID-19 hospitalization. Electronic health record (EHR)-based studies have been unable to distinguish between a hospitalization specifically for COVID-19 versus an incidental SARS-CoV-2 hospitalization. Although the need to improve classification of COVID-19 versus incidental SARS-CoV-2 is well understood, the magnitude of the problems has only been characterized in small, single-center studies. Furthermore, there have been no peer-reviewed studies evaluating methods for improving classification. OBJECTIVE: The aims of this study are to, first, quantify the frequency of incidental hospitalizations over the first 15 months of the pandemic in multiple hospital systems in the United States and, second, to apply electronic phenotyping techniques to automatically improve COVID-19 hospitalization classification. METHODS: From a retrospective EHR-based cohort in 4 US health care systems in Massachusetts, Pennsylvania, and Illinois, a random sample of 1123 SARS-CoV-2 PCR-positive patients hospitalized from March 2020 to August 2021 was manually chart-reviewed and classified as "admitted with COVID-19" (incidental) versus specifically admitted for COVID-19 ("for COVID-19"). EHR-based phenotyping was used to find feature sets to filter out incidental admissions. RESULTS: EHR-based phenotyped feature sets filtered out incidental admissions, which occurred in an average of 26% of hospitalizations (although this varied widely over time, from 0% to 75%). The top site-specific feature sets had 79%-99% specificity with 62%-75% sensitivity, while the best-performing across-site feature sets had 71%-94% specificity with 69%-81% sensitivity. CONCLUSIONS: A large proportion of SARS-CoV-2 PCR-positive admissions were incidental. Straightforward EHR-based phenotypes differentiated admissions, which is important to assure accurate public health reporting and research.

Accelerating diagnosis of Parkinson's disease through risk prediction.

BACKGROUND: Characterization of prediagnostic Parkinson's Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting. METHODS: We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window. RESULTS: We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles. CONCLUSIONS: Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.

International Changes in COVID-19 Clinical Trajectories Across 315 Hospitals and 6 Countries: Retrospective Cohort Study.

BACKGROUND: Many countries have experienced 2 predominant waves of COVID-19-related hospitalizations. Comparing the clinical trajectories of patients hospitalized in separate waves of the pandemic enables further understanding of the evolving epidemiology, pathophysiology, and health care dynamics of the COVID-19 pandemic. OBJECTIVE: In this retrospective cohort study, we analyzed electronic health record (EHR) data from patients with SARS-CoV-2 infections hospitalized in participating health care systems representing 315 hospitals across 6 countries. We compared hospitalization rates, severe COVID-19 risk, and mean laboratory values between patients hospitalized during the first and second waves of the pandemic. METHODS: Using a federated approach, each participating health care system extracted patient-level clinical data on their first and second wave cohorts and submitted aggregated data to the central site. Data quality control steps were adopted at the central site to correct for implausible values and harmonize units. Statistical analyses were performed by computing individual health care system effect sizes and synthesizing these using random effect meta-analyses to account for heterogeneity. We focused the laboratory analysis on C-reactive protein (CRP), ferritin, fibrinogen, procalcitonin, D-dimer, and creatinine based on their reported associations with severe COVID-19. RESULTS: Data were available for 79,613 patients, of which 32,467 were hospitalized in the first wave and 47,146 in the second wave. The prevalence of male patients and patients aged 50 to 69 years decreased significantly between the first and second waves. Patients hospitalized in the second wave had a 9.9% reduction in the risk of severe COVID-19 compared to patients hospitalized in the first wave (95% CI 8.5%-11.3%). Demographic subgroup analyses indicated that patients aged 26 to 49 years and 50 to 69 years; male and female patients; and black patients had significantly lower risk for severe disease in the second wave than in the first wave. At admission, the mean values of CRP were significantly lower in the second wave than in the first wave. On the seventh hospital day, the mean values of CRP, ferritin, fibrinogen, and procalcitonin were significantly lower in the second wave than in the first wave. In general, countries exhibited variable changes in laboratory testing rates from the first to the second wave. At admission, there was a significantly higher testing rate for D-dimer in France, Germany, and Spain. CONCLUSIONS: Patients hospitalized in the second wave were at significantly lower risk for severe COVID-19. This corresponded to mean laboratory values in the second wave that were more likely to be in typical physiological ranges on the seventh hospital day compared to the first wave. Our federated approach demonstrated the feasibility and power of harmonizing heterogeneous EHR data from multiple international health care systems to rapidly conduct large-scale studies to characterize how COVID-19 clinical trajectories evolve.

Authorship Correction: International Changes in COVID-19 Clinical Trajectories Across 315 Hospitals and 6 Countries: Retrospective Cohort Study.

[This corrects the article DOI: 10.2196/31400.].

Evaluation of the association of bariatric surgery with subsequent depression.

BACKGROUND/OBJECTIVES: Bariatric surgery is helpful in enabling sustained weight loss, but effects on depression are unclear. Reductions in depression-related symptoms and increases in suicide rate have both been observed after bariatric surgery, but these observations are confounded by the presence of pre-existing depression. The goal of this study is to evaluate the effect of bariatric surgery on subsequent depression diagnosis. SUBJECTS/METHODS: In this observational study, a prospective cohort study was simulated by evaluating depression risk based on diagnostic codes. An administrative database was utilized for this study, containing records and observations between 1 January 2008 through 29 February 2016 of enrolled patients in the United States. Individuals considered in this analysis were enrolled in a commercial health insurance program, observed for at least 6 months prior to surgery, and met the eligibility criteria for bariatric surgery. In all, 777,140 individuals were considered in total. RESULTS: Bariatric surgery was found to be significantly associated with subsequent depression relative to both non-surgery controls (HR = 1.31, 95% CI, 1.27-1.34, P < 2e-32) and non-bariatric abdominal surgery controls (HR = 2.15, 95% CI, 2.09-2.22, P < 2e-32). Patients with pre-surgical psychiatric screening had a reduced depression hazard ratio with respect to patients without (HR = 0.85, 95% CI, 0.81-0.89, P = 3.208e-12). Men were found to be more susceptible to post-bariatric surgery depression compared with women. Pre-surgical psychiatric evaluations reduced the magnitude of this effect. Relative to bariatric surgeries as a whole, vertical sleeve gastrectomy had a lower incidence of depression, while Roux-en Y Gastric Bypass and revision/removal surgeries had higher rates. CONCLUSIONS: In individuals without a history of depression, bariatric surgery is associated with subsequent diagnosis of depression. This study provides guidance for patients considering bariatric surgery and their clinicians in terms of evaluating potential risks and benefits of surgery.

Self-repairing symmetry in jellyfish through mechanically driven reorganization.

What happens when an animal is injured and loses important structures? Some animals simply heal the wound, whereas others are able to regenerate lost parts. In this study, we report a previously unidentified strategy of self-repair, where moon jellyfish respond to injuries by reorganizing existing parts, and rebuilding essential body symmetry, without regenerating what is lost. Specifically, in response to arm amputation, the young jellyfish of Aurelia aurita rearrange their remaining arms, recenter their manubria, and rebuild their muscular networks, all completed within 12 hours to 4 days. We call this process symmetrization. We find that symmetrization is not driven by external cues, cell proliferation, cell death, and proceeded even when foreign arms were grafted on. Instead, we find that forces generated by the muscular network are essential. Inhibiting pulsation using muscle relaxants completely, and reversibly, blocked symmetrization. Furthermore, we observed that decreasing pulse frequency using muscle relaxants slowed symmetrization, whereas increasing pulse frequency by lowering the magnesium concentration in seawater accelerated symmetrization. A mathematical model that describes the compressive forces from the muscle contraction, within the context of the elastic response from the mesoglea and the ephyra geometry, can recapitulate the recovery of global symmetry. Thus, self-repair in Aurelia proceeds through the reorganization of existing parts, and is driven by forces generated by its own propulsion machinery. We find evidence for symmetrization across species of jellyfish (Chrysaora pacifica, Mastigias sp., and Cotylorhiza tuberculata).

Chemical Space Mimicry for Drug Discovery.

We describe a new library generation method, Machine-based Identification of Molecules Inside Characterized Space (MIMICS), that generates sets of molecules inspired by a text-based input. MIMICS-generated libraries were found to preserve distributions of properties while simultaneously increasing structural diversity. Newly identified MIMICS-generated compounds were found to be bioactive as inhibitors of specific components of the unfolded protein response (UPR) and the VEGFR2 pathway in cell-based assays, thus confirming the applicability of this methodology toward drug design applications. Wider application of MIMICS could facilitate the efficient utilization of chemical space.

Profiling Metal Oxides with Lipids: Magnetic Liposomal Nanoparticles Displaying DNA and Proteins.

Metal oxides include many important materials with various surface properties. For biomedical and analytical applications, it is desirable to engineer their biocompatible interfaces. Herein, a phosphocholine liposome (DOPC) and its headgroup dipole flipped counterpart (DOCP) were mixed with ten common oxides. Using the calcein leakage assay, cryo-TEM, and ζ-potential measurement, these oxides were grouped into three types. The type 1 oxides (Fe3 O4 , TiO2 , ZrO2 , Y2 O3 , ITO, In2 O3 , and Mn2 O3 ) form supported bilayers only with DOCP. Type 2 (SiO2 ) forms supported bilayers only with DOPC; type 3 (ZnO and NiO) are cationic and damage lipid membranes. Magnetic Fe3 O4 nanoparticles were further studied for conjugation of fluorophores, proteins, and DNA to the supported DOCP bilayers via lipid headgroup labeling, covalent linking, or lipid insertion. Delivery of the conjugates to cells and selective DNA hybridization were demonstrated. This work provides a general solution for coating the type 1 oxides with a simple mixing in water, facilitating applications in biosensing, separation, and nanomedicine.

Tumor-Triggered Controlled Drug Release from Electrospun Fibers Using Inorganic Caps for Inhibiting Cancer Relapse.

A smart, tumor-trigged, controlled drug release using inorganic "caps" with CO3 (2-) functional groups in electrospun fibers is presented for inhibiting cancer relapse. When the drug-loaded intelligent electrospun fibers encounter pathological acidic environments, the inorganic gates react with the acids and produce CO2 gas, which enables water penetration into the core of the fibers to induce rapid drug release.

An operational guide to translational clinical machine learning in academic medical centers.

Few published data science tools are ever translated from academia to real-world clinical settings for which they were intended. One dimension of this problem is the software engineering task of turning published academic projects into tools that are usable at the bedside. Given the complexity of the data ecosystem in large health systems, this task often represents a significant barrier to the real-world deployment of data science tools for prospective piloting and evaluation. Many information technology companies have created Machine Learning Operations (MLOps) teams to help with such tasks at scale, but the low penetration of home-grown data science tools in regular clinical practice precludes the formation of such teams in healthcare organizations. Based on experiences deploying data science tools at two large academic medical centers (Beth Israel Deaconess Medical Center, Boston, MA; Mayo Clinic, Rochester, MN), we propose a strategy to facilitate this transition from academic product to operational tool, defining the responsibilities of the principal investigator, data scientist, machine learning engineer, health system IT administrator, and clinician end-user throughout the process. We first enumerate the technical resources and stakeholders needed to prepare for model deployment. We then propose an approach to planning how the final product will work from data extraction and analysis to visualization of model outputs. Finally, we describe how the team should execute on this plan. We hope to guide health systems aiming to deploy minimum viable data science tools and realize their value in clinical practice.

Neurological diagnoses in hospitalized COVID-19 patients associated with adverse outcomes: A multinational cohort study.

Few studies examining the patient outcomes of concurrent neurological manifestations during acute COVID-19 leveraged multinational cohorts of adults and children or distinguished between central and peripheral nervous system (CNS vs. PNS) involvement. Using a federated multinational network in which local clinicians and informatics experts curated the electronic health records data, we evaluated the risk of prolonged hospitalization and mortality in hospitalized COVID-19 patients from 21 healthcare systems across 7 countries. For adults, we used a federated learning approach whereby we ran Cox proportional hazard models locally at each healthcare system and performed a meta-analysis on the aggregated results to estimate the overall risk of adverse outcomes across our geographically diverse populations. For children, we reported descriptive statistics separately due to their low frequency of neurological involvement and poor outcomes. Among the 106,229 hospitalized COVID-19 patients (104,031 patients ≥18 years; 2,198 patients <18 years, January 2020-October 2021), 15,101 (14%) had at least one CNS diagnosis, while 2,788 (3%) had at least one PNS diagnosis. After controlling for demographics and pre-existing conditions, adults with CNS involvement had longer hospital stay (11 versus 6 days) and greater risk of (Hazard Ratio = 1.78) and faster time to death (12 versus 24 days) than patients with no neurological condition (NNC) during acute COVID-19 hospitalization. Adults with PNS involvement also had longer hospital stay but lower risk of mortality than the NNC group. Although children had a low frequency of neurological involvement during COVID-19 hospitalization, a substantially higher proportion of children with CNS involvement died compared to those with NNC (6% vs 1%). Overall, patients with concurrent CNS manifestation during acute COVID-19 hospitalization faced greater risks for adverse clinical outcomes than patients without any neurological diagnosis. Our global informatics framework using a federated approach (versus a centralized data collection approach) has utility for clinical discovery beyond COVID-19.

Trends in Medical Management of Moderately to Severely Active Ulcerative Colitis: A Nationwide Retrospective Analysis.

BACKGROUND: With an increasing number of therapeutic options available for the management of ulcerative colitis (UC), the variability in treatment and prescribing patterns is not well known. While recent guidelines have provided updates on how these therapeutic options should be used, patterns of long-term use of these drugs over the past 2 decades remain unclear. METHODS: We analyzed a retrospective, nationwide cohort of more than 1.7 million prescriptions for trends in prescribing behaviors and to evaluate practices suggested in guidelines relating to ordering biologics, step-up therapy, and combination therapy. The primary outcome was 30-day steroid-free remission and secondary outcomes included hospitalization, cost, and additional steroid usage. A pipeline was created to identify cohorts of patients under active UC medical management grouped by prescribing strategies to evaluate comparative outcomes between strategies. Cox proportional hazards and multivariate regression models were utilized to assess postexposure outcomes and adjust for confounders. RESULTS: Among 6 major drug categories, we noted major baseline differences in patient characteristics at first exposure corresponding to disease activity. We noted earlier use of biologics in patient trajectories (762 days earlier relative to UC diagnosis, 2018 vs 2008; P < .001) and greater overall use of biologics over time (2.53× more in 2018 vs 2008; P < .00001) . Among biologic-naive patients, adalimumab was associated with slightly lower rates of remission compared with infliximab or vedolizumab (odds ratio, 0.92; P < .005). Comparisons of patients with early biologic initiation to patients who transitioned to biologics from 5-aminosalicylic acid suggest lower steroid consumption for early biologic initiation (-761 mg prednisone; P < .001). Combination thiopurine-biologic therapy was associated with higher odds of remission compared with biologic monotherapy (odds ratio, 1.36; P = .01). CONCLUSIONS: As biologic drugs have become increasingly available for UC management, they have increasingly been used at earlier stages of disease management. Large-scale analyses of prescribing behaviors provide evidence supporting early use of biologics compared with step-up therapy and use of thiopurine and biologic combination therapy.

Population-scale analysis reveals patterns in prescribing trends for ulcerative colitis management. Findings include (1) earlier use of biologics in patient trajectories, (2) associations of step-up therapy with higher corticosteroid exposure, and (3) association of combination therapy with positive patient outcomes.

Quantifying the Prognostic Value of Preoperative Surgeon Intuition: Comparing Surgeon Intuition and Clinical Risk Prediction as Derived from the American College of Surgeons NSQIP Risk Calculator.

BACKGROUND: Surgical risk prediction models traditionally use patient attributes and measures of physiology to generate predictions about postoperative outcomes. However, the surgeon's assessment of the patient may be a valuable predictor, given the surgeon's ability to detect and incorporate factors that existing models cannot capture. We compare the predictive utility of surgeon intuition and a risk calculator derived from the American College of Surgeons (ACS) NSQIP. STUDY DESIGN: From January 10, 2021 to January 9, 2022, surgeons were surveyed immediately before performing surgery to assess their perception of a patient's risk of developing any postoperative complication. Clinical data were abstracted from ACS NSQIP. Both sources of data were independently used to build models to predict the likelihood of a patient experiencing any 30-day postoperative complication as defined by ACS NSQIP. RESULTS: Preoperative surgeon assessment was obtained for 216 patients. NSQIP data were available for 9,182 patients who underwent general surgery (January 1, 2017 to January 9, 2022). A binomial regression model trained on clinical data alone had an area under the receiver operating characteristic curve (AUC) of 0.83 (95% CI 0.80 to 0.85) in predicting any complication. A model trained on only preoperative surgeon intuition had an AUC of 0.70 (95% CI 0.63 to 0.78). A model trained on surgeon intuition and a subset of clinical predictors had an AUC of 0.83 (95% CI 0.77 to 0.89). CONCLUSIONS: Preoperative surgeon intuition alone is an independent predictor of patient outcomes; however, a risk calculator derived from ACS NSQIP is a more robust predictor of postoperative complication. Combining intuition and clinical data did not strengthen prediction.

Acute respiratory distress syndrome after SARS-CoV-2 infection on young adult population: International observational federated study based on electronic health records through the 4CE consortium.

PURPOSE: In young adults (18 to 49 years old), investigation of the acute respiratory distress syndrome (ARDS) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been limited. We evaluated the risk factors and outcomes of ARDS following infection with SARS-CoV-2 in a young adult population. METHODS: A retrospective cohort study was conducted between January 1st, 2020 and February 28th, 2021 using patient-level electronic health records (EHR), across 241 United States hospitals and 43 European hospitals participating in the Consortium for Clinical Characterization of COVID-19 by EHR (4CE). To identify the risk factors associated with ARDS, we compared young patients with and without ARDS through a federated analysis. We further compared the outcomes between young and old patients with ARDS. RESULTS: Among the 75,377 hospitalized patients with positive SARS-CoV-2 PCR, 1001 young adults presented with ARDS (7.8% of young hospitalized adults). Their mortality rate at 90 days was 16.2% and they presented with a similar complication rate for infection than older adults with ARDS. Peptic ulcer disease, paralysis, obesity, congestive heart failure, valvular disease, diabetes, chronic pulmonary disease and liver disease were associated with a higher risk of ARDS. We described a high prevalence of obesity (53%), hypertension (38%- although not significantly associated with ARDS), and diabetes (32%). CONCLUSION: Trough an innovative method, a large international cohort study of young adults developing ARDS after SARS-CoV-2 infection has been gather. It demonstrated the poor outcomes of this population and associated risk factor.

Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study.

Background: While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking. Methods: A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1-365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021. Findings: Advanced age (HR 2.77, 95%CI 2.53-3.04, p < 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03-4.17, p < 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55-5.00, p < 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14-1.39, p < 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37-0.46, p < 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17-1.54, p < 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20-1.58, p < 0.0001), male sex (HR 1.67, 95%CI 1.45-1.93, p < 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80-13.91, p < 0.0001), and hypertension (HR 1.22, 95%CI 1.10-1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32-1.67) and 365 days (RR 1.54, 95%CI 1.21-1.96) compared to COVID-19 patients with no AKI. Interpretation: COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery. Funding: Authors are supported by various funders, with full details stated in the acknowledgement section.

Distinguishing Admissions Specifically for COVID-19 from Incidental SARS-CoV-2 Admissions: A National EHR Research Consortium Study.

Admissions are generally classified as COVID-19 hospitalizations if the patient has a positive SARS-CoV-2 polymerase chain reaction (PCR) test. However, because 35% of SARS-CoV-2 infections are asymptomatic, patients admitted for unrelated indications with an incidentally positive test could be misclassified as a COVID-19 hospitalization. EHR-based studies have been unable to distinguish between a hospitalization specifically for COVID-19 versus an incidental SARS-CoV-2 hospitalization. From a retrospective EHR-based cohort in four US healthcare systems, a random sample of 1,123 SARS-CoV-2 PCR-positive patients hospitalized between 3/2020â€"8/2021 was manually chart-reviewed and classified as admitted-with-COVID-19 (incidental) vs. specifically admitted for COVID-19 (for-COVID-19). EHR-based phenotyped feature sets filtered out incidental admissions, which occurred in 26%. The top site-specific feature sets had 79-99% specificity with 62-75% sensitivity, while the best performing across-site feature set had 71-94% specificity with 69-81% sensitivity. A large proportion of SARS-CoV-2 PCR-positive admissions were incidental. Straightforward EHR-based phenotypes differentiated admissions, which is important to assure accurate public health reporting and research.

Changes in laboratory value improvement and mortality rates over the course of the pandemic: an international retrospective cohort study of hospitalised patients infected with SARS-CoV-2.

OBJECTIVE: To assess changes in international mortality rates and laboratory recovery rates during hospitalisation for patients hospitalised with SARS-CoV-2 between the first wave (1 March to 30 June 2020) and the second wave (1 July 2020 to 31 January 2021) of the COVID-19 pandemic. DESIGN, SETTING AND PARTICIPANTS: This is a retrospective cohort study of 83 178 hospitalised patients admitted between 7 days before or 14 days after PCR-confirmed SARS-CoV-2 infection within the Consortium for Clinical Characterization of COVID-19 by Electronic Health Record, an international multihealthcare system collaborative of 288 hospitals in the USA and Europe. The laboratory recovery rates and mortality rates over time were compared between the two waves of the pandemic. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was all-cause mortality rate within 28 days after hospitalisation stratified by predicted low, medium and high mortality risk at baseline. The secondary outcome was the average rate of change in laboratory values during the first week of hospitalisation. RESULTS: Baseline Charlson Comorbidity Index and laboratory values at admission were not significantly different between the first and second waves. The improvement in laboratory values over time was faster in the second wave compared with the first. The average C reactive protein rate of change was -4.72 mg/dL vs -4.14 mg/dL per day (p=0.05). The mortality rates within each risk category significantly decreased over time, with the most substantial decrease in the high-risk group (42.3% in March-April 2020 vs 30.8% in November 2020 to January 2021, p<0.001) and a moderate decrease in the intermediate-risk group (21.5% in March-April 2020 vs 14.3% in November 2020 to January 2021, p<0.001). CONCLUSIONS: Admission profiles of patients hospitalised with SARS-CoV-2 infection did not differ greatly between the first and second waves of the pandemic, but there were notable differences in laboratory improvement rates during hospitalisation. Mortality risks among patients with similar risk profiles decreased over the course of the pandemic. The improvement in laboratory values and mortality risk was consistent across multiple countries.

Illustrating potential effects of alternate control populations on real-world evidence-based statistical analyses.

OBJECTIVE: Case-control study designs are commonly used in retrospective analyses of real-world evidence (RWE). Due to the increasingly wide availability of RWE, it can be difficult to determine whether findings are robust or the result of testing multiple hypotheses. MATERIALS AND METHODS: We investigate the potential effects of modifying cohort definitions in a case-control association study between depression and type 2 diabetes mellitus. We used a large (>75 million individuals) de-identified administrative claims database to observe the effects of minor changes to the requirements of glucose and hemoglobin A1c tests in the control group. RESULTS: We found that small permutations to the criteria used to define the control population result in significant shifts in both the demographic structure of the identified cohort as well as the odds ratio of association. These differences remain present when testing against age- and sex-matched controls. DISCUSSION: Analyses of RWE need to be carefully designed to avoid issues of multiple testing. Minor changes to control cohorts can lead to significantly different results and have the potential to alter even prospective studies through selection bias. CONCLUSION: We believe this work offers strong support for the need for robust guidelines, best practices, and regulations around the use of observational RWE for clinical or regulatory decision-making.