We investigated the predictive value of geriatric assessment (GA) on overall survival (OS) for older adults with acute myelogenous leukemia (AML). Consecutive patients ≥ 60 years with newly diagnosed ...AML and planned intensive chemotherapy were enrolled at a single institution. Pretreatment GA included evaluation of cognition, depression, distress, physical function (PF) (self-reported and objectively measured), and comorbidity. Objective PF was assessed using the Short Physical Performance Battery (SPPB, timed 4-m walk, chair stands, standing balance) and grip strength. Cox proportional hazards models were fit for each GA measure as a predictor of OS. Among 74 patients, the mean age was 70 years, and 78.4% had an Eastern Cooperative Oncology Group (ECOG) score ≤ 1. OS was significantly shorter for participants who screened positive for impairment in cognition and objectively measured PF. Adjusting for age, gender, ECOG score, cytogenetic risk group, myelodysplastic syndrome, and hemoglobin, impaired cognition (Modified Mini-Mental State Exam < 77) and impaired objective PF (SPPB < 9) were associated with worse OS. GA methods, with a focus on cognitive and PF, improve risk stratification and may inform interventions to improve outcomes for older AML patients.
•Geriatric assessment, with a focus on cognitive and physical function, improves prediction of survival among older adults treated for AML.•Use of geriatric assessment may inform trial design and interventions to improve outcomes for older adults with AML.
Objective Health care generated data have become an important source for clinical and genomic research. Often, investigators create and iteratively refine phenotype algorithms to achieve high ...positive predictive values (PPVs) or sensitivity, thereby identifying valid cases and controls. These algorithms achieve the greatest utility when validated and shared by multiple health care systems.
Materials and Methods We report the current status and impact of the Phenotype KnowledgeBase (PheKB, http://phekb.org), an online environment supporting the workflow of building, sharing, and validating electronic phenotype algorithms. We analyze the most frequent components used in algorithms and their performance at authoring institutions and secondary implementation sites.
Results As of June 2015, PheKB contained 30 finalized phenotype algorithms and 62 algorithms in development spanning a range of traits and diseases. Phenotypes have had over 3500 unique views in a 6-month period and have been reused by other institutions. International Classification of Disease codes were the most frequently used component, followed by medications and natural language processing. Among algorithms with published performance data, the median PPV was nearly identical when evaluated at the authoring institutions (n = 44; case 96.0%, control 100%) compared to implementation sites (n = 40; case 97.5%, control 100%).
Discussion These results demonstrate that a broad range of algorithms to mine electronic health record data from different health systems can be developed with high PPV, and algorithms developed at one site are generally transportable to others.
Conclusion By providing a central repository, PheKB enables improved development, transportability, and validity of algorithms for research-grade phenotypes using health care generated data.
In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, ...whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.
Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on ...the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.
The role of serotonin in human brain function remains elusive due, at least in part, to our inability to measure rapidly the local concentration of this neurotransmitter. We used fast-scan cyclic ...voltammetry to infer serotonergic signaling from the striatum of 14 brains of human patients with Parkinson's disease. Here we report these novel measurements and show that they correlate with outcomes and decisions in a sequential investment game. We find that serotonergic concentrations transiently increase as a whole following negative reward prediction errors, while reversing when counterfactual losses predominate. This provides initial evidence that the serotonergic system acts as an opponent to dopamine signaling, as anticipated by theoretical models. Serotonin transients on one trial were also associated with actions on the next trial in a manner that correlated with decreased exposure to poor outcomes. Thus, the fluctuations observed for serotonin appear to correlate with the inhibition of over-reactions and promote persistence of ongoing strategies in the face of short-term environmental changes. Together these findings elucidate a role for serotonin in the striatum, suggesting it encodes a protective action strategy that mitigates risk and modulates choice selection particularly following negative environmental events.
The Michelson Interferometer for Global High-resolution Thermospheric Imaging (MIGHTI) instrument was built for launch and operation on the NASA Ionospheric Connection Explorer (ICON) mission. The ...instrument was designed to measure thermospheric horizontal wind velocity profiles and thermospheric temperature in altitude regions between 90 km and 300 km, during day and night. For the wind measurements it uses two perpendicular fields of view pointed at the Earth’s limb, observing the Doppler shift of the atomic oxygen red and green lines at 630.0 nm and 557.7 nm wavelength. The wavelength shift is measured using field-widened, temperature compensated Doppler Asymmetric Spatial Heterodyne (DASH) spectrometers, employing low order échelle gratings operating at two different orders for the different atmospheric lines. The temperature measurement is accomplished by a multichannel photometric measurement of the spectral shape of the molecular oxygen A-band around 762 nm wavelength. For each field of view, the signals of the two oxygen lines and the A-band are detected on different regions of a single, cooled, frame transfer charge coupled device (CCD) detector. On-board calibration sources are used to periodically quantify thermal drifts, simultaneously with observing the atmosphere. The MIGHTI requirements, the resulting instrument design and the calibration are described.
Mulitask-Temporal approach to develop predictive models using temporal information in EHR data. Display omitted
•We discuss methods to use temporal information in EHR data for predictive modeling.•We ...propose a multitask learning based approach.•We use our method to predict short-term progression of renal dysfunction.•We show that the importance of different predictors vary over time.•Our method was able to use temporal information in EHR data to improve performance.
Predictive models built using temporal data in electronic health records (EHRs) can potentially play a major role in improving management of chronic diseases. However, these data present a multitude of technical challenges, including irregular sampling of data and varying length of available patient history. In this paper, we describe and evaluate three different approaches that use machine learning to build predictive models using temporal EHR data of a patient.
The first approach is a commonly used non-temporal approach that aggregates values of the predictors in the patient’s medical history. The other two approaches exploit the temporal dynamics of the data. The two temporal approaches vary in how they model temporal information and handle missing data. Using data from the EHR of Mount Sinai Medical Center, we learned and evaluated the models in the context of predicting loss of estimated glomerular filtration rate (eGFR), the most common assessment of kidney function.
Our results show that incorporating temporal information in patient’s medical history can lead to better prediction of loss of kidney function. They also demonstrate that exactly how this information is incorporated is important. In particular, our results demonstrate that the relative importance of different predictors varies over time, and that using multi-task learning to account for this is an appropriate way to robustly capture the temporal dynamics in EHR data. Using a case study, we also demonstrate how the multi-task learning based model can yield predictive models with better performance for identifying patients at high risk of short-term loss of kidney function.
Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to ...assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.
NY-ESO-1 cancer testis (CT) antigen is an attractive candidate for immunotherapy as a result of its high immunogenicity. The aim of this study was to explore the potential for NY-ESO-1 antigen ...directed immunotherapy in triple negative breast cancer (TNBC) by determining the frequency of expression by immunohistochemistry (IHC) and the degree of inherent immunogenicity to NY-ESO-1.
168 TNBC and 47 ER+/HER2- primary breast cancer specimens were used to determine NY-ESO-1 frequency by IHC. As previous studies have shown that patients with a robust innate humoral immune response to CT antigens are more likely to develop CD8 T-cell responses to NY-ESO-1 peptides, we evaluated the degree to which patients with NY-ESO-1 expression had inherent immunogenicity by measuring antibodies. The relationship between NY-ESO-1 expression and CD8+ T lymphocytes was also examined.
The frequency of NY-ESO-1 expression in the TNBC cohort was 16% versus 2% in ER+/HER2- patients. A higher NY-ESO-1 score was associated with a younger age at diagnosis in the TNBC patients with NY-ESO-1 expression (p = 0.026). No differences in OS (p = 0.278) or PFS (p = 0.238) by NY-ESO-1 expression status were detected. Antibody responses to NY-ESO-1 were found in 73% of TNBC patients whose tumors were NY-ESO-1 positive. NY-ESO-1 positive patients had higher CD8 counts than negative patients (p = 0.018).
NY-ESO-1 is expressed in a substantial subset of TNBC patients and leads to a high humoral immune response in a large proportion of these individuals. Given these observations, patients with TNBC may benefit from targeted therapies directed against NY-ESO-1.
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