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BACKGROUND: As post kala-azar Dermal Leishmaniasis (PKDL) threatens the success of the Visceral Leishmaniasis (VL) elimination initiative, we aimed to investigate the PKDL burden, including an active search for PKDL in leprosy-negative skin lesion cases. We also investigated their health-seeking behavior and perceived level of stigma. METHODS: This was a cross-sectional survey among inhabitants in the VL-endemic villages of the five most VL-endemic upazilas. VL experts trained medical officers in Upazila Health Complexes (UHCs) and leprosy facilities in PKDL management. Frontline workers conducted house-to-house surveys, referring PKDL suspects to designated centers. Data analysis involved Epi Info version 7 and IBM SPSS Statistics 25. RESULTS: Among 472,435 screened individuals, 4022 had past VL (0.85%). Among the screened population, 82 were PKDL suspects, and 62 PKDL cases were confirmed. The overall PKDL burden was 1.3 (95% CI: 1.0-1.7) in the 10,000 population in the endemic villages. Male predominance and macular form of PKDL were observed. 39 PKDL patients perceived stigma of different levels. Only 27 of 62 (44%) had received PKDL treatment. Medicine's unavailability and side effects were a major reason behind treatment interruption. Active screening among 137 leprosy-negative PKDL suspects yielded 10 (7.3%) PKDL cases. CONCLUSIONS: The existence of PKDL cases in the VL endemic areas is a concern as those are inter-epidemic reservoirs. As per the WHO roadmap, the PKDL burden must be reduced by 70% and 100%, respectively, by 2026 and 2030. NKEP can take the current burden of 1.3 per 10,000 people in VL endemic villages as a baseline. Integrating active case detection for PKDL in leprosy hospitals and screening centers is feasible and worth deploying nationwide.
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Trained immunity may play a role in vaccine-induced protection against infections. We showed that the highly efficacious recombinant VZV-gE zoster vaccine (RZV) generated trained immunity in monocytes, natural killer (NK) cells, and dendritic cells (DCs) and that the less efficacious live zoster vaccine did not. RZV stimulated ex vivo gE-specific monocyte, DC and NK cell responses that did not correlate with CD4 + T-cell responses. These responses were also elicited in purified monocyte and NK cell cocultures stimulated with VZV-gE and persisted above prevaccination levels for ≥ 4 years post-RZV administration. RZV administration also increased ex vivo heterologous monocyte and NK cell responses to herpes simplex and cytomegalovirus antigens. ATAC-seq analysis and ex vivo TGFß1 supplementation and inhibition experiments demonstrated that decreased tgfß1 transcription resulting from RZV-induced chromatin modifications may explain the development of monocyte trained immunity. The role of RZV-trained immunity in protection against herpes zoster and other infections should be further studied.
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There is growing evidence that weather alters SARS-CoV-2 transmission, but it remains unclear what drives the phenomenon. One prevailing hypothesis is that people spend more time indoors in cooler weather, leading to increased spread of SARS-CoV-2 related to time spent in confined spaces and close contact with others. However, the evidence in support of that hypothesis is limited and, at times, conflicting. We use a mediation framework, and combine daily weather, COVID-19 hospital surveillance, cellphone-based mobility data and building footprints to estimate the relationship between daily indoor and outdoor weather conditions, mobility, and COVID-19 hospitalizations. We quantify the direct health impacts of weather on COVID-19 hospitalizations and the indirect effects of weather via time spent indoors away-from-home on COVID-19 hospitalizations within five Colorado counties between March 4th 2020 and January 31st 2021. We also evaluated the evidence for seasonal effect modification by comparing the results of all-season (using season as a covariate) to season-stratified models. Four weather conditions were associated with both time spent indoors away-from-home and 12-day lagged COVID-19 hospital admissions in one or more season: high minimum temperature (all-season), low maximum temperature (spring), low minimum absolute humidity (winter), and high solar radiation (all-season & winter). In our mediation analyses, we found evidence that changes in 12-day lagged hospital admissions were primarily via the direct effects of weather conditions, rather than via indirect effects by which weather changes time spent indoors away-from-home. Our findings do not support the hypothesis that weather impacted SARS-CoV-2 transmission via changes in mobility patterns during the first year of the pandemic. Rather, weather appears to have impacted SARS-CoV-2 transmission primarily via mechanisms other than human movement. We recommend further analysis of this phenomenon to determine whether these findings generalize to current SARS-CoV-2 transmission dynamics, as well as other seasonal respiratory pathogens.
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COVID-19 , Teléfono Celular , SARS-CoV-2 , Tiempo (Meteorología) , COVID-19/transmisión , COVID-19/epidemiología , Humanos , Hospitalización/estadística & datos numéricos , Estaciones del Año , Colorado/epidemiologíaRESUMEN
OBJECTIVES: To assess whether increasing levels of hospital stress-measured by intensive care unit (ICU) bed occupancy (primary), ventilators in use and emergency department (ED) overflow-were associated with decreasing COVID-19 ICU patient survival in Colorado ICUs during the pre-Delta, Delta and Omicron variant eras. DESIGN: A retrospective cohort study using discrete-time survival models, fit with generalised estimating equations. SETTING: 34 hospital systems in Colorado, USA, with the highest patient volume ICUs during the COVID-19 pandemic. PARTICIPANTS: 9196 non-paediatric SARS-CoV-2 patients in Colorado hospitals admitted once to an ICU between 1 August 2020 and 1 March 2022 and followed for 28 days. OUTCOME MEASURES: Death or discharge to hospice. RESULTS: For Delta-era COVID-19 ICU patients in Colorado, the odds of death were estimated to be 26% greater for patients exposed every day of their ICU admission to a facility experiencing its all-era 75th percentile ICU fullness or above, versus patients exposed for none of their days (OR: 1.26; 95% CI: 1.04 to 1.54; p=0.0102), adjusting for age, sex, length of ICU stay, vaccination status and hospital quality rating. For both Delta-era and Omicron-era patients, we also detected significantly increased mortality hazard associated with high ventilator utilisation rates and (in a subset of facilities) states of ED overflow. For pre-Delta-era patients, we estimated relatively null or even protective effects for the same fullness exposures, something which provides a meaningful contrast to previous studies that found increased hazards but were limited to pre-Delta study windows. CONCLUSIONS: Overall, and especially during the Delta era (when most Colorado facilities were at their fullest), increasing exposure to a fuller hospital was associated with an increasing mortality hazard for COVID-19 ICU patients.
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COVID-19 , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , SARS-CoV-2 , Humanos , COVID-19/mortalidad , COVID-19/epidemiología , Colorado/epidemiología , Estudios Retrospectivos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Ocupación de Camas/estadística & datos numéricos , Adulto , Servicio de Urgencia en Hospital/estadística & datos numéricosRESUMEN
Background: There is growing evidence that weather alters SARS-CoV-2 transmission, but it remains unclear what drives the phenomenon. One prevailing hypothesis is that people spend more time indoors in cooler weather, leading to increased spread of SARS-CoV-2 related to time spent in confined spaces and close contact with others. However, the evidence in support of that hypothesis is limited and, at times, conflicting. Objectives: We aim to evaluate the extent to which weather impacts COVID-19 via time spent away-from-home in indoor spaces, as compared to a direct effect of weather on COVID-19 hospitalization, independent of mobility. Methods: We use a mediation framework, and combine daily weather, COVID-19 hospital surveillance, cellphone-based mobility data and building footprints to estimate the relationship between daily indoor and outdoor weather conditions, mobility, and COVID-19 hospitalizations. We quantify the direct health impacts of weather on COVID-19 hospitalizations and the indirect effects of weather via time spent indoors away-from-home on COVID-19 hospitalizations within five Colorado counties between March 4th 2020 and January 31st 2021. Results: We found evidence that changes in 12-day lagged hospital admissions were primarily via the direct effects of weather conditions, rather than via indirect effects by which weather changes time spent indoors away-from-home. Sensitivity analyses evaluating time at home as a mediator were consistent with these conclusions. Discussion: Our findings do not support the hypothesis that weather impacted SARS-CoV-2 transmission via changes in mobility patterns during the first year of the pandemic. Rather, weather appears to have impacted SARS-CoV-2 transmission primarily via mechanisms other than human movement. We recommend further analysis of this phenomenon to determine whether these findings generalize to current SARS-CoV-2 transmission dynamics and other seasonal respiratory pathogens.
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This review presents the latest progress in photochemical and electrochemical reactions involving isatins. Isatin and its functionalized scaffolds e.g., oxindoles, spirooxindoles, and quinolines are privileged heterocycles as they are largely present in several agrochemical, natural products, and pharmaceuticals. Thus, the functionalization of isatins using sustainable approaches, i.e., electro- and photochemical methods is of recent research interest worldwide. In this review, we have discussed most of the important reactions of isatins based on types of bond formation involved under electro- and photochemical conditions over the last decade. The reaction mechanism for each reaction has been discussed in detail to offer an inclusive guide to readers. Lastly, a summary of current challenges and the future outlook toward the development of effective electrochemical and photochemical methods for the reaction of isatins is also presented.
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Deep learning (DL) algorithms used for DOTATATE PET lesion detection typically require large, well-annotated training datasets. These are difficult to obtain due to low incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and the high cost of manual annotation. Furthermore, networks trained and tested with data acquired from site specific PET/CT instrumentation, acquisition and processing protocols have reduced performance when tested with offsite data. This lack of generalizability requires even larger, more diverse training datasets. The objective of this study is to investigate the feasibility of improving DL algorithm performance by better matching the background noise in training datasets to higher noise, out-of-domain testing datasets. 68Ga-DOTATATE PET/CT datasets were obtained from two scanners: Scanner1, a state-of-the-art digital PET/CT (GE DMI PET/CT; n = 83 subjects), and Scanner2, an older-generation analog PET/CT (GE STE; n = 123 subjects). Set1, the data set from Scanner1, was reconstructed with standard clinical parameters (5 min; Q.Clear) and list-mode reconstructions (VPFXS 2, 3, 4, and 5-min). Set2, data from Scanner2 representing out-of-domain clinical scans, used standard iterative reconstruction (5 min; OSEM). A deep neural network was trained with each dataset: Network1 for Scanner1 and Network2 for Scanner2. DL performance (Network1) was tested with out-of-domain test data (Set2). To evaluate the effect of training sample size, we tested DL model performance using a fraction (25%, 50% and 75%) of Set1 for training. Scanner1, list-mode 2-min reconstructed data demonstrated the most similar noise level compared that of Set2, resulting in the best performance (F1 = 0.713). This was not significantly different compared to the highest performance, upper-bound limit using in-domain training for Network2 (F1 = 0.755; p-value = 0.103). Regarding sample size, the F1 score significantly increased from 25% training data (F1 = 0.478) to 100% training data (F1 = 0.713; p < 0.001). List-mode data from modern PET scanners can be reconstructed to better match the noise properties of older scanners. Using existing data and their associated annotations dramatically reduces the cost and effort in generating these datasets and significantly improves the performance of existing DL algorithms. List-mode reconstructions can provide an efficient, low-cost method to improve DL algorithm generalizability.
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The impact of B cell deficiency on the humoral and cellular responses to SARS-CoV2 mRNA vaccination remains a challenging and significant clinical management question. We evaluated vaccine-elicited serological and cellular responses in 1) healthy individuals who were pre-exposed to SARS-CoV-2 (n = 21), 2) healthy individuals who received a homologous booster (mRNA, n = 19; or Novavax, n = 19), and 3) persons with multiple sclerosis on B cell depletion therapy (MS-αCD20) receiving mRNA homologous boosting (n = 36). Pre-exposure increased humoral and CD4 T cellular responses in immunocompetent individuals. Novavax homologous boosting induced a significantly more robust serological response than mRNA boosting. MS-α CD20 had an intact IgA mucosal response and an enhanced CD8 T cell response to mRNA boosting compared with immunocompetent individuals. This enhanced cellular response was characterized by the expansion of only effector, not memory, T cells. The enhancement of CD8 T cells in the setting of B cell depletion suggests a regulatory mechanism between B and CD8 T cell vaccine responses.
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COVID-19 , Esclerosis Múltiple , Humanos , Vacunas contra la COVID-19 , ARN Viral , COVID-19/prevención & control , SARS-CoV-2 , ARN MensajeroRESUMEN
BACKGROUND: Researchers have used commercial databases containing residential addresses to reduce exposure misclassification in case-control studies. Our objective is to evaluate the potential systematic bias regarding case status when reconstructing residential locations from commercial databases. METHODS: Our study population of 3640 Colorado-born children includes 520 children diagnosed with acute lymphocytic leukemia between 2002 and 2019. We aligned addresses and date ranges obtained from LexisNexis with registry dates to determine three dichotomous outcomes: Found in LexisNexis, conception date found in LexisNexis, and reference date/diagnosis date found in LexisNexis. We applied logistic regression to determine whether outcomes differed by case status. RESULTS: Mothers of cases were 39% more likely to be found in LexisNexis than mothers of controls (OR = 1.39, 95% CI: 0.97, 2). Of the mothers found in LexisNexis, a conception address was 33% more likely (OR= 1.33, 95% CI: 1.06, 1.66) and a reference/diagnosis address was 60% more likely (OR= 1.60, 95% CI: 1.21, 2.12) to be found for mothers of cases than mothers of controls. CONCLUSION: This study indicates that use of commercial databases to reconstruct residential locations may systematically bias results in case-control studies of childhood cancers.
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Bases de Datos Factuales , Estudios de Factibilidad , Sistema de Registros , Humanos , Sistema de Registros/estadística & datos numéricos , Femenino , Niño , Estudios de Casos y Controles , Masculino , Preescolar , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Colorado/epidemiología , Lactante , Adolescente , Neoplasias/epidemiologíaRESUMEN
Advanced machine learning methods capable of capturing complex and nonlinear relationships can be used in biomedical research to accurately predict time-to-event outcomes. However, these methods have been criticized as "black boxes" that are not interpretable and thus are difficult to trust in making important clinical decisions. Explainable machine learning proposes the use of model-agnostic explainers that can be applied to predictions from any complex model. These explainers describe how a patient's characteristics are contributing to their prediction, and thus provide insight into how the model is arriving at that prediction. The specific application of these explainers to survival prediction models can be used to obtain explanations for (i) survival predictions at particular follow-up times, and (ii) a patient's overall predicted survival curve. Here, we present a model-agnostic approach for obtaining these explanations from any survival prediction model. We extend the local interpretable model-agnostic explainer framework for classification outcomes to survival prediction models. Using simulated data, we assess the performance of the proposed approaches under various settings. We illustrate application of the new methodology using prostate cancer data.
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Aprendizaje Automático , Modelos Estadísticos , Neoplasias de la Próstata , Humanos , Neoplasias de la Próstata/mortalidad , Masculino , Análisis de Supervivencia , Simulación por ComputadorRESUMEN
Multiplex imaging platforms have enabled the identification of the spatial organization of different types of cells in complex tissue or the tumor microenvironment. Exploring the potential variations in the spatial co-occurrence or colocalization of different cell types across distinct tissue or disease classes can provide significant pathological insights, paving the way for intervention strategies. However, the existing methods in this context either rely on stringent statistical assumptions or suffer from a lack of generalizability. We present a highly powerful method to study differential spatial co-occurrence of cell types across multiple tissue or disease groups, based on the theories of the Poisson point process and functional analysis of variance. Notably, the method accommodates multiple images per subject and addresses the problem of missing tissue regions, commonly encountered due to data-collection complexities. We demonstrate the superior statistical power and robustness of the method in comparison with existing approaches through realistic simulation studies. Furthermore, we apply the method to three real data sets on different diseases collected using different imaging platforms. In particular, one of these data sets reveals novel insights into the spatial characteristics of various types of colorectal adenoma.
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Simulación por Computador , Análisis de VarianzaRESUMEN
Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.
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Aprendizaje del Sistema de Salud , Medicina de Precisión , Humanos , Bancos de Muestras Biológicas , Colorado , GenómicaRESUMEN
OBJECTIVE: Lesion detection with positron emission tomography (PET) imaging is critical for tumor staging, treatment planning, and advancing novel therapies to improve patient outcomes, especially for neuroendocrine tumors (NETs). Current lesion detection methods often require manual cropping of regions/volumes of interest (ROIs/VOIs) a priori, or rely on multi-stage, cascaded models, or use multi-modality imaging to detect lesions in PET images. This leads to significant inefficiency, high variability and/or potential accumulative errors in lesion quantification. To tackle this issue, we propose a novel single-stage lesion detection method using only PET images. METHODS: We design and incorporate a new, plug-and-play codebook learning module into a U-Net-like neural network and promote lesion location-specific feature learning at multiple scales. We explicitly regularize the codebook learning with direct supervision at the network's multi-level hidden layers and enforce the network to learn multi-scale discriminative features with respect to predicting lesion positions. The network automatically combines the predictions from the codebook learning module and other layers via a learnable fusion layer. RESULTS: We evaluate the proposed method on a real-world clinical 68Ga-DOTATATE PET image dataset, and our method produces significantly better lesion detection performance than recent state-of-the-art approaches. CONCLUSION: We present a novel deep learning method for single-stage lesion detection in PET imaging data, with no ROI/VOI cropping in advance, no multi-stage modeling and no multi-modality data. SIGNIFICANCE: This study provides a new perspective for effective and efficient lesion identification in PET, potentially accelerating novel therapeutic regimen development for NETs and ultimately improving patient outcomes including survival.
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Tumores Neuroendocrinos , Compuestos Organometálicos , Humanos , Radioisótopos de Galio , Tomografía de Emisión de Positrones/métodos , Tumores Neuroendocrinos/patologíaRESUMEN
OBJECTIVE: Deep neural networks have been recently applied to lesion identification in fluorodeoxyglucose (FDG) positron emission tomography (PET) images, but they typically rely on a large amount of well-annotated data for model training. This is extremely difficult to achieve for neuroendocrine tumors (NETs), because of low incidence of NETs and expensive lesion annotation in PET images. The objective of this study is to design a novel, adaptable deep learning method, which uses no real lesion annotations but instead low-cost, list mode-simulated data, for hepatic lesion detection in real-world clinical NET PET images. METHODS: We first propose a region-guided generative adversarial network (RG-GAN) for lesion-preserved image-to-image translation. Then, we design a specific data augmentation module for our list-mode simulated data and incorporate this module into the RG-GAN to improve model training. Finally, we combine the RG-GAN, the data augmentation module and a lesion detection neural network into a unified framework for joint-task learning to adaptatively identify lesions in real-world PET data. RESULTS: The proposed method outperforms recent state-of-the-art lesion detection methods in real clinical 68Ga-DOTATATE PET images, and produces very competitive performance with the target model that is trained with real lesion annotations. CONCLUSION: With RG-GAN modeling and specific data augmentation, we can obtain good lesion detection performance without using any real data annotations. SIGNIFICANCE: This study introduces an adaptable deep learning method for hepatic lesion identification in NETs, which can significantly reduce human effort for data annotation and improve model generalizability for lesion detection with PET imaging.
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Curaduría de Datos , Tumores Neuroendocrinos , Humanos , Tomografía de Emisión de Positrones/métodos , Redes Neurales de la Computación , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
Introduction: Most childhood-onset SLE patients (cSLE) develop lupus nephritis (cLN), but only a small proportion achieve complete response to current therapies. The prognosis of children with LN and end-stage renal disease is particularly dire. Mortality rates within the first five years of renal replacement therapy may reach 22%. Thus, there is urgent need to decipher and target immune mechanisms that drive cLN. Despite the clear role of autoantibody production in SLE, targeted B cell therapies such as rituximab (anti-CD20) and belimumab (anti-BAFF) have shown only modest efficacy in cLN. While many studies have linked dysregulation of germinal center formation to SLE pathogenesis, other work supports a role for extrafollicular B cell activation in generation of pathogenic antibody secreting cells. However, whether extrafollicular B cell subsets and their T cell collaborators play a role in specific organ involvement in cLN and/or track with disease activity remains unknown. Methods: We analyzed high-dimensional mass cytometry and gene expression data from 24 treatment naïve cSLE patients at the time of diagnosis and longitudinally, applying novel computational tools to identify abnormalities associated with clinical manifestations (cLN) and disease activity (SLEDAI). Results: cSLE patients have an extrafollicular B cell expansion signature, with increased frequency of i) DN2, ii) Bnd2, iii) plasmablasts, and iv) peripheral T helper cells. Most importantly, we discovered that this extrafollicular signature correlates with disease activity in cLN, supporting extrafollicular T/B interactions as a mechanism underlying pediatric renal pathogenesis. Discussion: This study integrates established and emerging themes of extrafollicular B cell involvement in SLE by providing evidence for extrafollicular B and peripheral T helper cell expansion, along with elevated type 1 IFN activation, in a homogeneous cohort of treatment-naïve cSLE patients, a point at which they should display the most extreme state of their immune dysregulation.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Niño , Linfocitos B , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-InductoresRESUMEN
Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.
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BACKGROUND: In this paper, we are interested in interactions between a high-dimensional -omics dataset and clinical covariates. The goal is to evaluate the relationship between a phenotype of interest and a high-dimensional omics pathway, where the effect of the omics data depends on subjects' clinical covariates (age, sex, smoking status, etc.). For instance, metabolic pathways can vary greatly between sexes which may also change the relationship between certain metabolic pathways and a clinical phenotype of interest. We propose partitioning the clinical covariate space and performing a kernel association test within those partitions. To illustrate this idea, we focus on hierarchical partitions of the clinical covariate space and kernel tests on metabolic pathways. RESULTS: We see that our proposed method outperforms competing methods in most simulation scenarios. It can identify different relationships among clinical groups with higher power in most scenarios while maintaining a proper Type I error rate. The simulation studies also show a robustness to the grouping structure within the clinical space. We also apply the method to the COPDGene study and find several clinically meaningful interactions between metabolic pathways, the clinical space, and lung function. CONCLUSION: TreeKernel provides a simple and interpretable process for testing for relationships between high-dimensional omics data and clinical outcomes in the presence of interactions within clinical cohorts. The method is broadly applicable to many studies.
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Enfermedad Pulmonar Obstructiva Crónica , Humanos , Fenotipo , Simulación por ComputadorRESUMEN
In high-throughput spatial transcriptomics (ST) studies, it is of great interest to identify the genes whose level of expression in a tissue covaries with the spatial location of cells/spots. Such genes, also known as spatially variable genes (SVGs), can be crucial to the biological understanding of both structural and functional characteristics of complex tissues. Existing methods for detecting SVGs either suffer from huge computational demand or significantly lack statistical power. We propose a non-parametric method termed SMASH that achieves a balance between the above two problems. We compare SMASH with other existing methods in varying simulation scenarios demonstrating its superior statistical power and robustness. We apply the method to four ST datasets from different platforms uncovering interesting biological insights.
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Perfilación de la Expresión Génica , Transcriptoma , Transcriptoma/genética , Simulación por ComputadorRESUMEN
Deep neural networks have achieved excellent cell or nucleus quantification performance in microscopy images, but they often suffer from performance degradation when applied to cross-modality imaging data. Unsupervised domain adaptation (UDA) based on generative adversarial networks (GANs) has recently improved the performance of cross-modality medical image quantification. However, current GAN-based UDA methods typically require abundant target data for model training, which is often very expensive or even impossible to obtain for real applications. In this paper, we study a more realistic yet challenging UDA situation, where (unlabeled) target training data is limited and previous work seldom delves into cell identification. We first enhance a dual GAN with task-specific modeling, which provides additional supervision signals to assist with generator learning. We explore both single-directional and bidirectional task-augmented GANs for domain adaptation. Then, we further improve the GAN by introducing a differentiable, stochastic data augmentation module to explicitly reduce discriminator overfitting. We examine source-, target-, and dual-domain data augmentation for GAN enhancement, as well as joint task and data augmentation in a unified GAN-based UDA framework. We evaluate the framework for cell detection on multiple public and in-house microscopy image datasets, which are acquired with different imaging modalities, staining protocols and/or tissue preparations. The experiments demonstrate that our method significantly boosts performance when compared with the reference baseline, and it is superior to or on par with fully supervised models that are trained with real target annotations. In addition, our method outperforms recent state-of-the-art UDA approaches by a large margin on different datasets.
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Técnicas Histológicas , Aprendizaje , Humanos , Microscopía , Redes Neurales de la Computación , Coloración y Etiquetado , Procesamiento de Imagen Asistido por ComputadorRESUMEN
Cytochrome P450 aromatase (AROM) and steroid (estrone (E1)/dehydroepiandrosterone (DHEA)) sulfatase (STS) are the two key enzymes responsible for the biosynthesis of estrogens in human, and maintenance of the critical balance between androgens and estrogens. Human AROM, an integral membrane protein of the endoplasmic reticulum, is a member of the Fe-heme containing cytochrome P450 superfamily having a cysteine thiolate as the fifth Fe-coordinating ligand. It is the only enzyme known to catalyze the conversion of androgens with non-aromatic A-rings to estrogens characterized by the aromatic A-ring. Human STS, also an integral membrane protein of the endoplasmic reticulum, is a Ca2+-dependent enzyme that catalyzes the hydrolysis of sulfate esters of E1 and DHEA to yield the respective unconjugated steroids, the precursors of the most potent forms of estrogens and androgens, namely, 17ß-estradiol (E2), 16α,17ß-estriol (E3), testosterone (TST) and dihydrotestosterone (DHT). Expression of these steroidogenic enzymes locally within various organs and tissues of the endocrine, reproductive, and central nervous systems is the key for maintaining high levels of the reproductive steroids. Thus, the enzymes have been drug targets for the prevention and treatment of diseases associated with steroid hormone excesses, especially in breast and prostate malignancies and endometriosis. Both AROM and STS have been the subjects of vigorous research for the past six decades. In this article, we review the procedures of their extraction and purification from human term placenta are described in detail, along with the activity assays.