RESUMEN
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by the combination of T-cell lineage and the presence of immaturity marker(s). Sometimes, the most common immaturity markers for initial flow cytometry screening in T-ALL may be negative, which can be a diagnostic pitfall. When a lack of common first-line immaturity markers is encountered in combination with gamma/delta T-cell receptor expression, a misdiagnosis of mature gamma-delta T-cell leukemia/lymphoma could be rendered. Here, we discuss two T-ALL cases with the absence of common flow cytometry immaturity markers and positive gamma/delta receptor expression.
RESUMEN
OBJECTIVE: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, no replicated genetic loci have been identified, and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype. The objective of this study was to perform a well-powered genetic study of TRD. METHODS: Using receipt of electroconvulsive therapy (ECT) as a surrogate for TRD, the authors applied standard machine learning methods to electronic health record data to derive predicted probabilities of receiving ECT. These probabilities were then applied as a quantitative trait in a genome-wide association study of 154,433 genotyped patients across four large biobanks. RESULTS: Heritability estimates ranged from 2% to 4.2%, and significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index. Two genome-wide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. CONCLUSIONS: This work provides support for the utility of estimation of disease probability for genomic investigation and provides insights into the genetic architecture and biology of TRD.
Asunto(s)
Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Terapia Electroconvulsiva , Estudio de Asociación del Genoma Completo , Humanos , Trastorno Depresivo Resistente al Tratamiento/genética , Trastorno Depresivo Resistente al Tratamiento/terapia , Femenino , Masculino , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/terapia , Persona de Mediana Edad , Aprendizaje Automático , Adulto , Fenotipo , Anciano , Índice de Masa Corporal , Esquizofrenia/genética , Esquizofrenia/terapiaRESUMEN
While eosinophilic esophagitis (EOE) is defined by histologic presence of eosinophils, a few studies have established the presence of mast cells in EOE and even shown their correlation with symptom persistence despite resolution of eosinophils. Expression of aberrant mast cell markers CD25 and CD2 have not been studied in EOE. This study quantifies the number of hotspot cells per high power field expressing CKIT/CD117, tryptase, CD25, CD2 and CD3 by immunohistochemical stains in endoscopic esophageal biopsies of the following three cohorts: (1) established and histologically confirmed EOE, (2) suspected EOE with biopsies negative for eosinophils, and (3) no history of or suspicion for EOE with histologically unremarkable biopsies. In this study, mast cells were highlighted by CKIT and tryptase in EOE, and not seen in other clinically mimicking cases. There were also significantly higher densities of CD25 and pan-T-cell marker staining in EOE cases. These findings suggest an inflammatory cellular milieu in EOE, beyond just eosinophils, that can be demonstrated by immunohistochemistry, and that invite further study into the role that these cells may play in EOE.
Asunto(s)
Biomarcadores , Esofagitis Eosinofílica , Eosinófilos , Subunidad alfa del Receptor de Interleucina-2 , Mastocitos , Linfocitos T , Humanos , Esofagitis Eosinofílica/patología , Esofagitis Eosinofílica/metabolismo , Esofagitis Eosinofílica/diagnóstico , Mastocitos/patología , Mastocitos/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Masculino , Biomarcadores/metabolismo , Femenino , Linfocitos T/patología , Linfocitos T/metabolismo , Eosinófilos/patología , Eosinófilos/metabolismo , Adulto , Inmunohistoquímica/métodos , Biopsia , Persona de Mediana Edad , Niño , Adolescente , Triptasas/metabolismo , Adulto Joven , Esófago/patología , Esófago/metabolismo , PreescolarRESUMEN
Educational attainment (EduYears), a heritable trait often used as a proxy for cognitive ability, is associated with various health and social outcomes. Previous genome-wide association studies (GWASs) on EduYears have been focused on samples of European (EUR) genetic ancestries. Here we present the first large-scale GWAS of EduYears in people of East Asian (EAS) ancestry (n = 176,400) and conduct a cross-ancestry meta-analysis with EduYears GWAS in people of EUR ancestry (n = 766,345). EduYears showed a high genetic correlation and power-adjusted transferability ratio between EAS and EUR. We also found similar functional enrichment, gene expression enrichment and cross-trait genetic correlations between two populations. Cross-ancestry fine-mapping identified refined credible sets with a higher posterior inclusion probability than single population fine-mapping. Polygenic prediction analysis in four independent EAS and EUR cohorts demonstrated transferability between populations. Our study supports the need for further research on diverse ancestries to increase our understanding of the genetic basis of educational attainment.
Asunto(s)
Éxito Académico , Pueblos del Este de Asia , Humanos , Escolaridad , Estudio de Asociación del Genoma Completo , Herencia Multifactorial/genética , Población BlancaRESUMEN
Genome-wide association studies (GWASs) have identified tens of thousands of genetic loci associated with human complex traits. However, the majority of GWASs were conducted in individuals of European ancestries. Failure to capture global genetic diversity has limited genomic discovery and has impeded equitable delivery of genomic knowledge to diverse populations. Here we report findings from 102,900 individuals across 36 human quantitative traits in the Taiwan Biobank (TWB), a major biobank effort that broadens the population diversity of genetic studies in East Asia. We identified 968 novel genetic loci, pinpointed novel causal variants through statistical fine-mapping, compared the genetic architecture across TWB, Biobank Japan, and UK Biobank, and evaluated the utility of cross-phenotype, cross-population polygenic risk scores in disease risk prediction. These results demonstrated the potential to advance discovery through diversifying GWAS populations and provided insights into the common genetic basis of human complex traits in East Asia.
RESUMEN
Aging is associated with nonresolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a proresolving ligand that acts through the G-protein-coupled receptor called GPR18. Unbiased RNA sequencing revealed increased Gpr18 expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lacked GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, increased monocyte-derived macrophages, and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly on the bone marrow to increase monocyte-macrophage progenitors. A transplantation assay further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice. Transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, this study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.
Asunto(s)
Médula Ósea , Hígado Graso , Persona de Mediana Edad , Humanos , Ratones , Animales , Anciano , Médula Ósea/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Envejecimiento , Cirrosis Hepática , Fibrosis , Colágeno/genética , Ratones Endogámicos C57BLRESUMEN
Genome-wide association studies (GWASs) have been mostly conducted in populations of European ancestry, which currently limits the transferability of their findings to other populations. Here, we show, through theory, simulations and applications to real data, that adjustment of GWAS analyses for polygenic scores (PGSs) increases the statistical power for discovery across all ancestries. We applied this method to analyze seven traits available in three large biobanks with participants of East Asian ancestry (n = 340,000 in total) and report 139 additional associations across traits. We also present a two-stage meta-analysis strategy whereby, in contributing cohorts, a PGS-adjusted GWAS is rerun using PGSs derived from a first round of a standard meta-analysis. On average, across traits, this approach yields a 1.26-fold increase in the number of detected associations (range 1.07- to 1.76-fold increase). Altogether, our study demonstrates the value of using PGSs to increase the power of GWASs in underrepresented populations and promotes such an analytical strategy for future GWAS meta-analyses.
Asunto(s)
Pueblos del Este de Asia , Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Humanos , Estudio de Asociación del Genoma Completo/métodos , Fenotipo , Polimorfismo de Nucleótido Simple , Pueblos del Este de Asia/genéticaRESUMEN
Syphilis is a bacterial infection commonly transmitted by sexual contact. It has variable manifestations and can mimic other disease processes or infections. This report presents the case of a 48-year-old HIV-positive male who was referred to our head and neck clinic with complaints of tonsillar hypertrophy and ulceration accompanied by a one-month history of ipsilateral cervical lymphadenopathy and facial pain in the setting of recent unexplained weight loss and abnormal radiographic imaging of the neck. In-office tonsillar biopsy and fine-needle aspiration of a neck mass revealed a non-diagnostic atypical lymphoid proliferation. Surgical pathology following an open biopsy in the operating room showed Treponema pallidum infection, which was diagnostic for secondary syphilis.
RESUMEN
BACKGROUND: Hospital-based biobanks are being increasingly considered as a resource for translating polygenic risk scores (PRS) into clinical practice. However, since these biobanks originate from patient populations, there is a possibility of bias in polygenic risk estimation due to overrepresentation of patients with higher frequency of healthcare interactions. METHODS: PRS for schizophrenia, bipolar disorder, and depression were calculated using summary statistics from the largest available genomic studies for a sample of 24 153 European ancestry participants in the Mass General Brigham (MGB) Biobank. To correct for selection bias, we fitted logistic regression models with inverse probability (IP) weights, which were estimated using 1839 sociodemographic, clinical, and healthcare utilization features extracted from electronic health records of 1 546 440 non-Hispanic White patients eligible to participate in the Biobank study at their first visit to the MGB-affiliated hospitals. RESULTS: Case prevalence of bipolar disorder among participants in the top decile of bipolar disorder PRS was 10.0% (95% CI 8.8-11.2%) in the unweighted analysis but only 6.2% (5.0-7.5%) when selection bias was accounted for using IP weights. Similarly, case prevalence of depression among those in the top decile of depression PRS was reduced from 33.5% (31.7-35.4%) to 28.9% (25.8-31.9%) after IP weighting. CONCLUSIONS: Non-random selection of participants into volunteer biobanks may induce clinically relevant selection bias that could impact implementation of PRS in research and clinical settings. As efforts to integrate PRS in medical practice expand, recognition and mitigation of these biases should be considered and may need to be optimized in a context-specific manner.
Asunto(s)
Trastorno Bipolar , Humanos , Predisposición Genética a la Enfermedad , Sesgo de Selección , Estudio de Asociación del Genoma Completo , Trastorno Bipolar/epidemiología , Trastorno Bipolar/genética , Herencia Multifactorial , Factores de RiesgoRESUMEN
Information on vaccination rates and factors associated with adherence in persons with HIV (PWH) is limited. We report vaccine adherence in 653 adult PWH attending an urban Infectious Disease Clinic from January 2015 to December 2021. Vaccines evaluated included influenza, pneumococcal, tetanus, hepatitis A virus (HAV) and hepatitis B virus (HBV), human papillomavirus (HPV), and zoster vaccines. Vaccine reminders were triggered at every visit, and all vaccines were accessible in the clinic. The mean age was 50 y (±SD 13), male gender was 78.6%, and black race was 74.3%. The overall adherence to all recommended vaccines was 63.6%. Vaccine adherence was >90% for influenza, pneumococcal, and tetanus, >80% for HAV and HBV, and ≥60% for HPV and zoster vaccines. The main predictor of adherence to all vaccines was ≥2 annual clinic visits (odds ratio [OR] 3.45; 95% confidence interval [CI] 2.36-5.05; p < .001). Other predictors included an assigned primary care provider within the system (OR 2.89 [95% CI 1.71-5.00, p < .001]) and CD4 >200 cell/mm3 at entry into care (OR 1.91 [95% CI 1.24-2.94, p = .0003]). Retention in care combined with vaccine reminders and accessibility of vaccines in the clinic can achieve high vaccine uptake in PWH.
Asunto(s)
Infecciones por VIH , Virus de la Hepatitis A , Vacuna contra el Herpes Zóster , Herpes Zóster , Vacunas contra la Influenza , Gripe Humana , Infecciones por Papillomavirus , Tétanos , Adulto , Humanos , Masculino , Persona de Mediana Edad , Gripe Humana/complicaciones , Infecciones por Papillomavirus/complicaciones , Vacunación , Toxoide Tetánico , Vacunas Neumococicas , Streptococcus pneumoniae , Virus de la Hepatitis B , Virus del Papiloma Humano , Infecciones por VIH/complicaciones , Herpes Zóster/complicacionesRESUMEN
Patients with rectal cancer undergo more repeat biopsies compared to those with nonrectal colon cancer prior to management. We investigated the factors driving the higher frequency of repeat biopsies in patients with rectal cancer. We compared clinicopathologic features of diagnostic and nondiagnostic (in regard to invasion) rectal (n = 64) and colonic (n = 57) biopsies from colorectal cancer patients and characterized corresponding resections. Despite similar diagnostic yield, repeat biopsy was more common in rectal carcinoma, especially in patients receiving neoadjuvant therapy (p < 0.05). The presence of desmoplasia (odds ratio 12.9, p < 0.05) was a strong predictor of making a diagnosis of invasion in both rectal and nonrectal colon cancer biopsies. Diagnostic biopsies had more desmoplasia, intramucosal carcinoma component and marked inflammation, and less low-grade dysplasia component (p < 0.05). Diagnostic yield of biopsy was higher for tumors with high-grade tumor budding, mucosal involvement by high-grade dysplasia/intramucosal carcinoma without low-grade dysplasia and diffuse surface desmoplasia irrespective of tumor location. Sample size, amount of benign tissue, appearance, and T stage did not affect diagnostic yield. Repeat biopsy of rectal cancer is primarily driven by management implications. Diagnostic yield in colorectal cancer biopsies is multifactorial and is not due to differing pathologists' diagnostic approach per tumor site. For rectal tumors, a multidisciplinary strategic approach is warranted to avoid repeat biopsy when unnecessary.
RESUMEN
BACKGROUND: Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations. METHODS: We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts. RESULTS: The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance. CONCLUSIONS: By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.
Asunto(s)
Diabetes Mellitus Tipo 2 , Estudio de Asociación del Genoma Completo , Teorema de Bayes , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Humanos , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. METHODS: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for 'all epilepsy', 'focal epilepsy', and 'genetic generalised epilepsy' (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. FINDINGS: Cases of presumed monogenic severe epilepsy had an increased PRS for 'all epilepsy' (p<0.0001), 'focal epilepsy' (p<0.0001), and 'GGE' (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. INTERPRETATION: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders. FUNDING: Science foundation Ireland, Human Genome Research Institute; National Heart, Lung, and Blood Institute; German Research Foundation.
Asunto(s)
Epilepsia Generalizada , Discapacidad Intelectual , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Variación Genética , Humanos , Herencia Multifactorial , Mutación , FenotipoRESUMEN
Colorectal cancer is the third leading cause of cancer-related death, and its incidence is rising in the younger patient population. In the past decade, research has unveiled several processes (underlying tumorigenesis, many of which involve interactions between tumor cells and the surrounding tissue or tumor microenvironment (TME). Interactions between components of the TME are mediated at a sub-microscopic level. However, the endpoint of those interactions results in morphologic changes which can be readily assessed at microscopic examination of biopsy and resection specimens. Among these morphologic changes, alteration to the tumor stroma is a new, important determinant of colorectal cancer progression. Different methodologies to estimate the proportion of tumor stroma relative to tumor cells, or tumor stroma ratio (TSR), have been developed. Subsequent validation has supported the prognostic value, reproducibility and feasibility of TSR in various subgroups of colorectal cancer. In this manuscript, we review the literature surrounding TME in colorectal cancer, with a focus on tumor stroma ratio.
Asunto(s)
Adenocarcinoma , Neoplasias Colorrectales , Neoplasias Primarias Secundarias , Adenocarcinoma/patología , Neoplasias Colorrectales/patología , Humanos , Reproducibilidad de los Resultados , Microambiente TumoralRESUMEN
Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) have been conducted predominantly in individuals of European descent, the limited transferability of PRS reduces their clinical value in non-European populations, and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research have expanded the scale of non-European GWAS, although most remain underpowered. Here, we present a new PRS construction method, PRS-CSx, which improves cross-population polygenic prediction by integrating GWAS summary statistics from multiple populations. PRS-CSx couples genetic effects across populations via a shared continuous shrinkage (CS) prior, enabling more accurate effect size estimation by sharing information between summary statistics and leveraging linkage disequilibrium diversity across discovery samples, while inheriting computational efficiency and robustness from PRS-CS. We show that PRS-CSx outperforms alternative methods across traits with a wide range of genetic architectures, cross-population genetic overlaps and discovery GWAS sample sizes in simulations, and improves the prediction of quantitative traits and schizophrenia risk in non-European populations.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genética de Población , Estudio de Asociación del Genoma Completo/métodos , Humanos , Desequilibrio de Ligamiento , Herencia Multifactorial/genética , Factores de RiesgoRESUMEN
The Taiwan Biobank (TWB) is an ongoing prospective study of >150,000 individuals aged 20-70 in Taiwan. A comprehensive list of phenotypes was collected for each consented participant at recruitment and follow-up visits through structured interviews and physical measurements. Biomarkers and genetic data were generated from blood and urine samples. We present here an overview of TWB's genetic data quality, population structure, and familial relationship, which consists of predominantly Han Chinese ancestry, and highlight its important attributes and genetic findings thus far. A linkage to Taiwan's National Health Insurance database of >25 years and other registries is underway to enrich the phenotypic spectrum and enable deep and longitudinal genetic investigations. TWB provides one of the largest biobank resources for biomedical and public health research in East Asia that will contribute to our understanding of the genetic basis of health and disease in global populations through collaborative studies with other biobanks.
Asunto(s)
Transfusión Sanguínea/métodos , Duodeno , Embolización Terapéutica/métodos , Hemorragia Gastrointestinal , Enfermedad Relacionada con Inmunoglobulina G4 , Linfangiectasia Intestinal , Adulto , Biopsia/métodos , Diagnóstico Diferencial , Duodeno/diagnóstico por imagen , Duodeno/patología , Endoscopía del Sistema Digestivo/métodos , Endosonografía/métodos , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/fisiopatología , Hemorragia Gastrointestinal/terapia , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/inmunología , Linfangiectasia Intestinal/complicaciones , Linfangiectasia Intestinal/diagnóstico por imagen , Linfangiectasia Intestinal/fisiopatología , Linfangiectasia Intestinal/terapia , Linfografía/métodos , Masculino , Imagen Multimodal/métodos , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: There have been few reports regarding the frequency and types of preanalytical errors in stat laboratories, in particular those occurring in the satellite laboratory setting. The impact of this error type on laboratory performance in this environment is largely unknown. We assessed the performance of a stat laboratory serving a population of predominantly elderly patients with suspected or established diagnoses of cancer using Six Sigma methodology and compared the results to previous work on this subject. METHODS: We performed an observational retrospective study using data from the period 2013-2020. The clinical setting was a satellite laboratory supporting an outpatient medical clinic. The type and frequency of each type of preanalytical error were compiled and were used to derive the quarterly error rate. Overall and quarterly performance were calculated using Six Sigma methodology. RESULTS: During the study period 1314 preanalytical errors were identified from 247,271 laboratory tests (0.5% of total test volume). There was a steady decrease in the error rate over the course of the study period, ranging from 1.4% in 2013 to 0.14% in 2020, despite a 290% increase in quarterly test volume during this period. The most common error types encountered were order error, hemolysis, collection error, and lab accident. CONCLUSION: 1) The overall performance of a satellite laboratory with a stat testing menu is comparable to hospital-based laboratory stat testing. 2) The most frequent error types encountered in satellite laboratory stat testing differ from those found in hospital-based laboratories. 3) There was an overall improvement in laboratory performance based on Six Sigma methodology.
Asunto(s)
Laboratorios de Hospital , Gestión de la Calidad Total , Anciano , Técnicas de Laboratorio Clínico , Errores Diagnósticos , Hemólisis , Humanos , Estudios RetrospectivosRESUMEN
Objectives: To characterize the temporal characteristics of clinical variables with time lock to mortality and build a predictive model of mortality associated with COVID-19 using clinical variables. Design: Retrospective cohort study of the temporal characteristics of clinical variables with time lock to mortality. Setting: Stony Brook University Hospital (New York) and Tongji Hospital. Patients: Patients with confirmed positive for severe acute respiratory syndrome coronavirus-2 using polymerase chain reaction testing. Patients from the Stony Brook University Hospital data were used for training (80%, N = 1,002) and testing (20%, N = 250), and 375 patients from the Tongji Hospital (Wuhan, China) data were used for testing. Intervention: None. Measurements and Main Results: Longitudinal clinical variables were analyzed as a function of days from outcome with time-lock-to-day of death (non-survivors) or discharge (survivors). A predictive model using the significant earliest predictors was constructed. Performance was evaluated using receiver operating characteristics area under the curve (AUC). The predictive model found lactate dehydrogenase, lymphocytes, procalcitonin, D-dimer, C-reactive protein, respiratory rate, and white-blood cells to be early predictors of mortality. The AUC for the zero to 9 days prior to outcome were: 0.99, 0.96, 0.94, 0.90, 0.82, 0.75, 0.73, 0.77, 0.79, and 0.73, respectively (Stony Brook Hospital), and 1.0, 0.86, 0.88, 0.96, 0.91, 0.62, 0.67, 0.50, 0.63, and 0.57, respectively (Tongji Hospital). In comparison, prediction performance using hospital admission data was poor (AUC = 0.59). Temporal fluctuations of most clinical variables, indicative of physiological and biochemical instability, were markedly higher in non-survivors compared to survivors (p < 0.001). Conclusion: This study identified several clinical markers that demonstrated a temporal progression associated with mortality. These variables accurately predicted death within a few days prior to outcome, which provides objective indication that closer monitoring and interventions may be needed to prevent deterioration.