A novel Bayesian generative approach for estimating tumor dynamics from published studies.

Tumor growth inhibition (TGI) modeling attempts to describe the time course changes in tumor size for patients undergoing cancer therapy. TGI models present several advantages over traditional exposure-response models that are based explicitly on clinical end points and have become a popular tool in the pharmacometrics community. Unfortunately, the data required to fit TGI models, namely longitudinal tumor measurements, are sparse or often not available in literature or publicly accessible databases. On the contrary, common end points such as progression-free survival (PFS) and objective response rate (ORR) are directly derived from longitudinal tumor measurements and are routinely published. To this end, a Bayesian generative model relating underlying tumor dynamics to summary PFS and ORR data is introduced to learn TGI model parameters using only published summary data. The parameterized model can describe the tumor dynamics, quantify treatment effect, and account for differences in the study population. The utility of this model is shown by applying it to several published studies, and learned parameters are combined to simulate an in silico trial of a novel combination therapy in a novel setting.

Associations of longitudinal D-Dimer and Factor II on early trauma survival risk.

BACKGROUND: Trauma-induced coagulopathy (TIC) is a disorder that occurs in one-third of severely injured trauma patients, manifesting as increased bleeding and a 4X risk of mortality. Understanding the mechanisms driving TIC, clinical risk factors are essential to mitigating this coagulopathic bleeding and is therefore essential for saving lives. In this retrospective, single hospital study of 891 trauma patients, we investigate and quantify how two prominently described phenotypes of TIC, consumptive coagulopathy and hyperfibrinolysis, affect survival odds in the first 25 h, when deaths from TIC are most prevalent. METHODS: We employ a joint survival model to estimate the longitudinal trajectories of the protein Factor II (% activity) and the log of the protein fragment D-Dimer ([Formula: see text]g/ml), representative biomarkers of consumptive coagulopathy and hyperfibrinolysis respectively, and tie them together with patient outcomes. Joint models have recently gained popularity in medical studies due to the necessity to simultaneously track continuously measured biomarkers as a disease evolves, as well as to associate them with patient outcomes. In this work, we estimate and analyze our joint model using Bayesian methods to obtain uncertainties and distributions over associations and trajectories. RESULTS: We find that a unit increase in log D-Dimer increases the risk of mortality by 2.22 [1.57, 3.28] fold while a unit increase in Factor II only marginally decreases the risk of mortality by 0.94 [0.91,0.96] fold. This suggests that, while managing consumptive coagulopathy and hyperfibrinolysis both seem to affect survival odds, the effect of hyperfibrinolysis is much greater and more sensitive. Furthermore, we find that the longitudinal trajectories, controlling for many fixed covariates, trend differently for different patients. Thus, a more personalized approach is necessary when considering treatment and risk prediction under these phenotypes. CONCLUSION: This study reinforces the finding that hyperfibrinolysis is linked with poor patient outcomes regardless of factor consumption levels. Furthermore, it quantifies the degree to which measured D-Dimer levels correlate with increased risk. The single hospital, retrospective nature can be understood to specify the results to this particular hospital's patients and protocol in treating trauma patients. Expanding to a multi-hospital setting would result in better estimates about the underlying nature of consumptive coagulopathy and hyperfibrinolysis with survival, regardless of protocol. Individual trajectories obtained with these estimates can be used to provide personalized dynamic risk prediction when making decisions regarding management of blood factors.

Adherent Use of Digital Health Trackers Is Associated with Weight Loss.

We study the association between weight fluctuation and activity tracking in an on-line population of thousands of individuals using digital health trackers (1,749 ≤ N ≤ 14,411, depending on the activity tracker considered) with millions of recorded activities (119,292 ≤ N ≤ 2,221,382) over the years 2013-2015. In a first between-subject analysis, we found a positive association between activity tracking frequency and weight loss. Users who log food with moderate frequency lost an additional 0.63% (CI [0.55, 0.72]; p < .001) of their body weight per month relative to low frequency loggers. Frequent workout loggers lost an additional 0.38% (CI [0.20, 0.56]; p < .001) and frequent weight loggers lost an additional 0.40% (CI [0.33, 0.47]; p < .001) as compared to infrequent loggers. In a subsequent within-subject analysis on a subset of the population (799 ≤ N ≤ 6,052) with sufficient longitudinal data, we used fixed effect models to explore the temporal relationship between a change in tracking adherence and weight change. We found that for the same individual, weight loss is significantly higher during periods of high adherence to tracking vs. periods of low adherence: +2.74% of body weight lost per month (CI [2.68, 2.81]; p < .001) during adherent weight tracking, +1.35% per month (CI [1.26, 1.43]; p < .001) during adherent food tracking, and +0.60% per month (CI [0.44, 0.76]; p < .001) during adherent workout tracking. The findings suggest that adherence to activity tracking can be utilized as a convenient real-time predictor of weight fluctuations, enabling large-scale, personalized intervention strategies.

On the Inference of Functional Circadian Networks Using Granger Causality.

Being able to infer one way direct connections in an oscillatory network such as the suprachiastmatic nucleus (SCN) of the mammalian brain using time series data is difficult but crucial to understanding network dynamics. Although techniques have been developed for inferring networks from time series data, there have been no attempts to adapt these techniques to infer directional connections in oscillatory time series, while accurately distinguishing between direct and indirect connections. In this paper an adaptation of Granger Causality is proposed that allows for inference of circadian networks and oscillatory networks in general called Adaptive Frequency Granger Causality (AFGC). Additionally, an extension of this method is proposed to infer networks with large numbers of cells called LASSO AFGC. The method was validated using simulated data from several different networks. For the smaller networks the method was able to identify all one way direct connections without identifying connections that were not present. For larger networks of up to twenty cells the method shows excellent performance in identifying true and false connections; this is quantified by an area-under-the-curve (AUC) 96.88%. We note that this method like other Granger Causality-based methods, is based on the detection of high frequency signals propagating between cell traces. Thus it requires a relatively high sampling rate and a network that can propagate high frequency signals.