Modeling molecular development of breast cancer in canine mammary tumors.

Understanding the changes in diverse molecular pathways underlying the development of breast tumors is critical for improving diagnosis, treatment, and drug development. Here, we used RNA-profiling of canine mammary tumors (CMTs) coupled with a robust analysis framework to model molecular changes in human breast cancer. Our study leveraged a key advantage of the canine model, the frequent presence of multiple naturally occurring tumors at diagnosis, thus providing samples spanning normal tissue and benign and malignant tumors from each patient. We showed human breast cancer signals, at both expression and mutation level, are evident in CMTs. Profiling multiple tumors per patient enabled by the CMT model allowed us to resolve statistically robust transcription patterns and biological pathways specific to malignant tumors versus those arising in benign tumors or shared with normal tissues. We showed that multiple histological samples per patient is necessary to effectively capture these progression-related signatures, and that carcinoma-specific signatures are predictive of survival for human breast cancer patients. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we provide FREYA, a robust data processing pipeline and statistical analyses framework.

Interactive Big Data Resource to Elucidate Human Immune Pathways and Diseases.

Many functionally important interactions between genes and proteins involved in immunological diseases and processes are unknown. The exponential growth in public high-throughput data offers an opportunity to expand this knowledge. To unlock human-immunology-relevant insight contained in the global biomedical research effort, including all public high-throughput datasets, we performed immunological-pathway-focused Bayesian integration of a comprehensive, heterogeneous compendium comprising 38,088 genome-scale experiments. The distillation of this knowledge into immunological networks of functional relationships between molecular entities (ImmuNet), and tools to mine this resource, are accessible to the public at http://immunet.princeton.edu. The predictive capacity of ImmuNet, established by rigorous statistical validation, is easily accessed by experimentalists to generate data-driven hypotheses. We demonstrate the power of this approach through the identification of unique host-virus interaction responses, and we show how ImmuNet complements genetic studies by predicting disease-associated genes. ImmuNet should be widely beneficial for investigating the mechanisms of the human immune system and immunological diseases.

Comparing Clinician Estimates versus a Statistical Tool for Predicting Risk of Death within 45 Days of Admission for Cancer Patients.

OBJECTIVES: While clinical practice guidelines recommend that oncologists discuss goals of care with patients who have advanced cancer, it is estimated that less than 20% of individuals admitted to the hospital with high-risk cancers have end-of-life discussions with their providers. While there has been interest in developing models for mortality prediction to trigger such discussions, few studies have compared how such models compare with clinical judgment to determine a patient's mortality risk. METHODS: This study is a prospective analysis of 1,069 solid tumor medical oncology hospital admissions (n = 911 unique patients) from February 7 to June 7, 2022, at Memorial Sloan Kettering Cancer Center. Electronic surveys were sent to hospitalists, advanced practice providers, and medical oncologists the first afternoon following a hospital admission and they were asked to estimate the probability that the patient would die within 45 days. Provider estimates of mortality were compared with those from a predictive model developed using a supervised machine learning methodology, and incorporated routine laboratory, demographic, biometric, and admission data. Area under the receiver operating characteristic curve (AUC), calibration and decision curves were compared between clinician estimates and the model predictions. RESULTS: Within 45 days following hospital admission, 229 (25%) of 911 patients died. The model performed better than the clinician estimates (AUC 0.834 vs. 0.753, p < 0.0001). Integrating clinician predictions with the model's estimates further increased the AUC to 0.853 (p < 0.0001). Clinicians overestimated risk whereas the model was extremely well-calibrated. The model demonstrated net benefit over a wide range of threshold probabilities. CONCLUSION: The inpatient prognosis at admission model is a robust tool to assist clinical providers in evaluating mortality risk, and it has recently been implemented in the electronic medical record at our institution to improve end-of-life care planning for hospitalized cancer patients.

Tissue-specific functional networks for prioritizing phenotype and disease genes.

Integrated analyses of functional genomics data have enormous potential for identifying phenotype-associated genes. Tissue-specificity is an important aspect of many genetic diseases, reflecting the potentially different roles of proteins and pathways in diverse cell lineages. Accounting for tissue specificity in global integration of functional genomics data is challenging, as "functionality" and "functional relationships" are often not resolved for specific tissue types. We address this challenge by generating tissue-specific functional networks, which can effectively represent the diversity of protein function for more accurate identification of phenotype-associated genes in the laboratory mouse. Specifically, we created 107 tissue-specific functional relationship networks through integration of genomic data utilizing knowledge of tissue-specific gene expression patterns. Cross-network comparison revealed significantly changed genes enriched for functions related to specific tissue development. We then utilized these tissue-specific networks to predict genes associated with different phenotypes. Our results demonstrate that prediction performance is significantly improved through using the tissue-specific networks as compared to the global functional network. We used a testis-specific functional relationship network to predict genes associated with male fertility and spermatogenesis phenotypes, and experimentally confirmed one top prediction, Mbyl1. We then focused on a less-common genetic disease, ataxia, and identified candidates uniquely predicted by the cerebellum network, which are supported by both literature and experimental evidence. Our systems-level, tissue-specific scheme advances over traditional global integration and analyses and establishes a prototype to address the tissue-specific effects of genetic perturbations, diseases and drugs.

Analysis of a Remote Monitoring Program for Symptoms Among Adults With Cancer Receiving Antineoplastic Therapy.

IMPORTANCE: Electronic patient-reported outcomes (ePROs) may have the potential to improve cancer care delivery by enhancing patient quality of life, reducing acute care visits, and extending overall survival. However, the optimal cadence of ePRO assessments is unknown. OBJECTIVE: To determine patient response preferences and the clinical value associated with a daily cadence for ePROs for patients receiving antineoplastic treatment. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study of adult patients undergoing antineoplastic treatment assessed a remote monitoring program using ePROs that was developed to manage cancer therapy-related symptoms. ePRO data submitted between October 16, 2018 to February 29, 2020, from a single regional site within the Memorial Sloan Kettering Cancer Center network were included. Data were analyzed from April 2020 to January 2022. EXPOSURE: While undergoing active treatment, patients received a daily ePRO assessment that, based on patient responses, generated yellow (moderate) or red (severe) symptom alerts that were sent to clinicians. MAIN OUTCOMES AND MEASURES: The main outcomes assessed included patient response rate, symptom alert frequency, and an analysis of the clinical value of daily ePROs. RESULTS: A total of 217 patients (median [range] age, 66 [31-92] years; 103 [47.5%] women and 114 [52.5%] men) initiating antineoplastic therapy at high risk for symptoms were monitored for a median (range) of 91 (2-369) days. Most patients had thoracic (59 patients [27.2%]), head and neck (48 patients [22.1%]), or gastrointestinal (43 patients [19.8%]) malignant neoplasms. Of 14 603 unique symptom assessments completed, 7349 (50.3%) generated red or yellow symptom alerts. Symptoms commonly generating alerts included pain (665 assessments [23.0%]) and functional status (465 assessments [16.1%]). Most assessments (8438 assessments [57.8%]) were completed at home during regular clinic hours (ie, 9 am-5 pm), with higher response rates on weekdays (58.4%; 95% CI, 57.5%-59.5%) than on weekend days (51.3%; 95% CI, 49.5%-53.1%). Importantly, 284 of 630 unique red alerts (45.1%) surfaced without a prior yellow alert for the same symptom within the prior 7 days; symptom severity fluctuated over the course of a week, and symptom assessments generating a red alert were followed by an acute care visit within 7 days 8.7% of the time compared with 2.9% for assessments without a red alert. CONCLUSIONS AND RELEVANCE: These findings suggest that daily ePRO assessments were associated with increased insight into symptom management in patients undergoing antineoplastic treatment and symptom alerts were associated with risk of acute care.

Building a Clinically Relevant Risk Model: Predicting Risk of a Potentially Preventable Acute Care Visit for Patients Starting Antineoplastic Treatment.

PURPOSE: To create a risk prediction model that identifies patients at high risk for a potentially preventable acute care visit (PPACV). PATIENTS AND METHODS: We developed a risk model that used electronic medical record data from initial visit to first antineoplastic administration for new patients at Memorial Sloan Kettering Cancer Center from January 2014 to September 2018. The final time-weighted least absolute shrinkage and selection operator model was chosen on the basis of clinical and statistical significance. The model was refined to predict risk on the basis of 270 clinically relevant data features spanning sociodemographics, malignancy and treatment characteristics, laboratory results, medical and social history, medications, and prior acute care encounters. The binary dependent variable was occurrence of a PPACV within the first 6 months of treatment. There were 8,067 observations for new-start antineoplastic therapy in our training set, 1,211 in the validation set, and 1,294 in the testing set. RESULTS: A total of 3,727 patients experienced a PPACV within 6 months of treatment start. Specific features that determined risk were surfaced in a web application, riskExplorer, to enable clinician review of patient-specific risk. The positive predictive value of a PPACV among patients in the top quartile of model risk was 42%. This quartile accounted for 35% of patients with PPACVs and 51% of potentially preventable inpatient bed days. The model C-statistic was 0.65. CONCLUSION: Our clinically relevant model identified the patients responsible for 35% of PPACVs and more than half of the inpatient beds used by the cohort. Additional research is needed to determine whether targeting these high-risk patients with symptom management interventions could improve care delivery by reducing PPACVs.

Misery Loves Company: Presenting Symptom Clusters to Urgent Care by Patients Receiving Antineoplastic Therapy.

PURPOSE: The Centers for Medicare & Medicaid Services (CMS) identifies suboptimal management of treatment toxicities as a care gap and proposes the measurement of hospital performance on the basis of emergency department visits for 10 common symptoms. Current management strategies do not address symptom co-occurrence. METHODS: We evaluated symptom co-occurrence in three patient cohorts that presented to a cancer hospital urgent care center in 2016. We examined both the CMS-identified symptoms and an expanded clinician-identified set defined as symptoms that could be safely managed in the outpatient setting if identified early and managed proactively. The cohorts included patients who presented with a CMS-defined symptom within 30 days of treatment, patients who presented within 30 days of treatment with a symptom from the expanded set, and patients who presented with a symptom from the expanded set within 30 days of treatment start. Symptom co-occurrence was measured by Jaccard index. A community detection algorithm was used to identify symptom clusters on the basis of a random walk process, and network visualizations were used to illustrate symptom dynamics. RESULTS: There were 6,429 presentations in the CMS symptom-defined cohort. The network analysis identified two distinct symptom clusters centered around pain and fever. In the expanded symptom cohort, there were 5,731 visits and six symptom clusters centered around fever, emesis/nausea, fatigue, deep vein thrombosis, pain, and ascites. For patients who newly initiated treatment, there were 1,154 visits and four symptom clusters centered around fever, nausea/emesis, fatigue, and deep vein thrombosis. CONCLUSION: Uncontrolled symptoms are associated with unplanned acute care. Recognition of the complexity of symptom co-occurrence can drive improved management strategies.