Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Multi-population generalizability of a deep learning-based chest radiograph severity score for COVID-19.

To tune and test the generalizability of a deep learning-based model for assessment of COVID-19 lung disease severity on chest radiographs (CXRs) from different patient populations. A published convolutional Siamese neural network-based model previously trained on hospitalized patients with COVID-19 was tuned using 250 outpatient CXRs. This model produces a quantitative measure of COVID-19 lung disease severity (pulmonary x-ray severity (PXS) score). The model was evaluated on CXRs from 4 test sets, including 3 from the United States (patients hospitalized at an academic medical center (N = 154), patients hospitalized at a community hospital (N = 113), and outpatients (N = 108)) and 1 from Brazil (patients at an academic medical center emergency department (N = 303)). Radiologists from both countries independently assigned reference standard CXR severity scores, which were correlated with the PXS scores as a measure of model performance (Pearson R). The Uniform Manifold Approximation and Projection (UMAP) technique was used to visualize the neural network results. Tuning the deep learning model with outpatient data showed high model performance in 2 United States hospitalized patient datasets (R = 0.88 and R = 0.90, compared to baseline R = 0.86). Model performance was similar, though slightly lower, when tested on the United States outpatient and Brazil emergency department datasets (R = 0.86 and R = 0.85, respectively). UMAP showed that the model learned disease severity information that generalized across test sets. A deep learning model that extracts a COVID-19 severity score on CXRs showed generalizable performance across multiple populations from 2 continents, including outpatients and hospitalized patients.

QU-BraTS: MICCAI BraTS 2020 Challenge on Quantifying Uncertainty in Brain Tumor Segmentation - Analysis of Ranking Scores and Benchmarking Results.

Deep learning (DL) models have provided state-of-the-art performance in various medical imaging benchmarking challenges, including the Brain Tumor Segmentation (BraTS) challenges. However, the task of focal pathology multi-compartment segmentation (e.g., tumor and lesion sub-regions) is particularly challenging, and potential errors hinder translating DL models into clinical workflows. Quantifying the reliability of DL model predictions in the form of uncertainties could enable clinical review of the most uncertain regions, thereby building trust and paving the way toward clinical translation. Several uncertainty estimation methods have recently been introduced for DL medical image segmentation tasks. Developing scores to evaluate and compare the performance of uncertainty measures will assist the end-user in making more informed decisions. In this study, we explore and evaluate a score developed during the BraTS 2019 and BraTS 2020 task on uncertainty quantification (QU-BraTS) and designed to assess and rank uncertainty estimates for brain tumor multi-compartment segmentation. This score (1) rewards uncertainty estimates that produce high confidence in correct assertions and those that assign low confidence levels at incorrect assertions, and (2) penalizes uncertainty measures that lead to a higher percentage of under-confident correct assertions. We further benchmark the segmentation uncertainties generated by 14 independent participating teams of QU-BraTS 2020, all of which also participated in the main BraTS segmentation task. Overall, our findings confirm the importance and complementary value that uncertainty estimates provide to segmentation algorithms, highlighting the need for uncertainty quantification in medical image analyses. Finally, in favor of transparency and reproducibility, our evaluation code is made publicly available at https://github.com/RagMeh11/QU-BraTS.

Assessing the Trustworthiness of Saliency Maps for Localizing Abnormalities in Medical Imaging.

PURPOSE: To evaluate the trustworthiness of saliency maps for abnormality localization in medical imaging. MATERIALS AND METHODS: Using two large publicly available radiology datasets (Society for Imaging Informatics in Medicine-American College of Radiology Pneumothorax Segmentation dataset and Radiological Society of North America Pneumonia Detection Challenge dataset), the performance of eight commonly used saliency map techniques were quantified in regard to (a) localization utility (segmentation and detection), (b) sensitivity to model weight randomization, (c) repeatability, and (d) reproducibility. Their performances versus baseline methods and localization network architectures were compared, using area under the precision-recall curve (AUPRC) and structural similarity index measure (SSIM) as metrics. RESULTS: All eight saliency map techniques failed at least one of the criteria and were inferior in performance compared with localization networks. For pneumothorax segmentation, the AUPRC ranged from 0.024 to 0.224, while a U-Net achieved a significantly superior AUPRC of 0.404 (P < .005). For pneumonia detection, the AUPRC ranged from 0.160 to 0.519, while a RetinaNet achieved a significantly superior AUPRC of 0.596 (P <.005). Five and two saliency methods (of eight) failed the model randomization test on the segmentation and detection datasets, respectively, suggesting that these methods are not sensitive to changes in model parameters. The repeatability and reproducibility of the majority of the saliency methods were worse than localization networks for both the segmentation and detection datasets. CONCLUSION: The use of saliency maps in the high-risk domain of medical imaging warrants additional scrutiny and recommend that detection or segmentation models be used if localization is the desired output of the network.Keywords: Technology Assessment, Technical Aspects, Feature Detection, Convolutional Neural Network (CNN) Supplemental material is available for this article. © RSNA, 2021.

Improvement and Multi-Population Generalizability of a Deep Learning-Based Chest Radiograph Severity Score for COVID-19.

PURPOSE: To improve and test the generalizability of a deep learning-based model for assessment of COVID-19 lung disease severity on chest radiographs (CXRs) from different patient populations. MATERIALS AND METHODS: A published convolutional Siamese neural network-based model previously trained on hospitalized patients with COVID-19 was tuned using 250 outpatient CXRs. This model produces a quantitative measure of COVID-19 lung disease severity (pulmonary x-ray severity (PXS) score). The model was evaluated on CXRs from four test sets, including 3 from the United States (patients hospitalized at an academic medical center (N=154), patients hospitalized at a community hospital (N=113), and outpatients (N=108)) and 1 from Brazil (patients at an academic medical center emergency department (N=303)). Radiologists from both countries independently assigned reference standard CXR severity scores, which were correlated with the PXS scores as a measure of model performance (Pearson r). The Uniform Manifold Approximation and Projection (UMAP) technique was used to visualize the neural network results. RESULTS: Tuning the deep learning model with outpatient data improved model performance in two United States hospitalized patient datasets (r=0.88 and r=0.90, compared to baseline r=0.86). Model performance was similar, though slightly lower, when tested on the United States outpatient and Brazil emergency department datasets (r=0.86 and r=0.85, respectively). UMAP showed that the model learned disease severity information that generalized across test sets. CONCLUSIONS: Performance of a deep learning-based model that extracts a COVID-19 severity score on CXRs improved using training data from a different patient cohort (outpatient versus hospitalized) and generalized across multiple populations.