We study the diffusion of information in an overlaying social-physical network. Specifically, we consider the following set-up: There is a physical information network where information spreads ...amongst people through conventional communication media (e.g., face-to-face communication, phone calls), and conjoint to this physical network, there are online social networks where information spreads via web sites such as Facebook, Twitter, FriendFeed, YouTube, etc. We quantify the size and the critical threshold of information epidemics in this conjoint social-physical network by assuming that information diffuses according to the SIR epidemic model. One interesting finding is that even if there is no percolation in the individual networks, percolation (i.e., information epidemics) can take place in the conjoint social-physical network. We also show, both analytically and experimentally, that the fraction of individuals who receive an item of information (started from an arbitrary node) is significantly larger in the conjoint social-physical network case, as compared to the case where the networks are disjoint. These findings reveal that conjoining the physical network with online social networks can have a dramatic impact on the speed and scale of information diffusion.
We consider a cyber-physical system consisting of two interacting networks, i.e., a cyber network overlaying a physical network. It is envisioned that these systems are more vulnerable to attacks ...since node failures in one network may result in (due to the interdependence) failures in the other network, causing a cascade of failures that would potentially lead to the collapse of the entire infrastructure. The robustness of interdependent systems against this sort of catastrophic failure hinges heavily on the allocation of the (interconnecting) links that connect nodes in one network to nodes in the other network. In this paper, we characterize the optimum inter-link allocation strategy against random attacks in the case where the topology of each individual network is unknown. In particular, we analyze the "regular" allocation strategy that allots exactly the same number of bidirectional internetwork links to all nodes in the system. We show, both analytically and experimentally, that this strategy yields better performance (from a network resilience perspective) compared to all possible strategies, including strategies using random allocation, unidirectional interlinks, etc.
Many in silico predictors of genetic variant pathogenicity have been previously developed, but there is currently no standard application of these algorithms for variant assessment. Using 4,094 ...ClinVar-curated missense variants in clinically actionable genes, we evaluated the accuracy and yield of benign and deleterious evidence in 5 in silico meta-predictors, as well as agreement of SIFT and PolyPhen2, and report the derived thresholds for the best performing predictor(s). REVEL and BayesDel outperformed all other meta-predictors (CADD, MetaSVM, Eigen), with higher positive predictive value, comparable negative predictive value, higher yield, and greater overall prediction performance. Agreement of SIFT and PolyPhen2 resulted in slightly higher yield but lower overall prediction performance than REVEL or BayesDel. Our results support the use of gene-level rather than generalized thresholds, when gene-level thresholds can be estimated. Our results also support the use of 2-sided thresholds, which allow for uncertainty, rather than a single, binary cut-point for assigning benign and deleterious evidence. The gene-level 2-sided thresholds we derived for REVEL or BayesDel can be used to assess in silico evidence for missense variants in accordance with current classification guidelines.
Modern systems are increasingly dependent upon and interacting with each other, and become interdependent networks. These interdependent networks may exhibit some interesting and even surprising ...behaviors due to the interdependency and the interplay between the constituent systems. In this article we focus on two important phenomena, namely cascading failure in cyber-physical systems (CPS) and information cascade in coupled social networks. Specifically, cascading failures may occur in CPS that exhibit functional interdependency between two constituent systems (e.g. smart grid); information cascade may happen in multiple social networks that are coupled together by so-called multi-membership individuals. This article explores these two types of cascading effects in interdependent networks by reviewing existing studies in the literature. We review different models in the literature to study the two types of cascading effects in interdependent networks, and highlight the key findings from these studies.
In this paper, we study distributed scheduling in multihop multiple-input-multiple-output (MIMO) networks. We first develop a "MIMO-pipe" model that provides the upper layers a set of rates and ...signal-to-interference-plus-noise ratio (SINR) requirements that capture the rate-reliability tradeoff in MIMO communications. The main thrust of this paper is then dedicated to developing distributed carrier sense multiple access (CSMA) algorithms for MIMO-pipe scheduling under the SINR interference model. We choose the SINR model over the extensively studied protocol-based interference models because it more naturally captures the impact of interference in wireless networks. The coupling among the links caused by the interference under the SINR model makes the problem of devising distributed scheduling algorithms very challenging. To that end, we explore the CSMA algorithms for MIMO-pipe scheduling from two perspectives. We start with an idealized continuous-time CSMA network, where control messages can be exchanged in a collision-free manner, and devise a CSMA-based link scheduling algorithm that can achieve throughput optimality under the SINR model. Next, we consider a discrete-time CSMA network, where the message exchanges suffer from collisions. For this more challenging case, we develop a "conservative" scheduling algorithm by imposing a more stringent SINR constraint on the MIMO-pipe model. We show that the proposed conservative scheduling achieves an efficiency ratio bounded from below.
Major immunotherapy challenges include a limited number of predictive biomarkers and the unusual imaging features post-therapy, such as pseudo-progression, which denote immune infiltrate-mediated ...tumor enlargement. Such phenomena confound clinical decision-making, since the cancer may eventually regress, and the patient should stay on treatment. We prospectively evaluated serial, blood-derived cell-free DNA (cfDNA) (baseline and 2-3 weeks post-immune checkpoint inhibitors ICIs) for variant allele frequency (VAF) and blood tumor mutation burden (bTMB) changes (next-generation sequencing) (N = 84 evaluable patients, diverse cancers). Low vs. high cfDNA-derived average adjusted ΔVAF (calculated by a machine-learning model) was an independent predictor of higher clinical benefit rate (stable disease ≥6 months/complete/partial response) (69.2% vs. 22.5%), and longer median progression-free (10.1 vs. 2.25 months) and overall survival (not reached vs. 6.1 months) (all P < .001, multivariate). bTMB changes did not correlate with outcomes. Therefore, early dynamic changes in cfDNA-derived VAF were a powerful predictor of pan-cancer immunotherapy outcomes.
Liquid biopsy to predict immunotherapy response.
To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers.
Three patients were vaccinated ...with 1.0×10(8) plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6×10(8) pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro.
p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T-cell compartment (P=0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1+ T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P=0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent.
p53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit.
This phase 1/2 study assessed the augmentation of reduced-intensity conditioning (RIC) with total marrow and lymph node irradiation (TMLI), for peripheral blood stem cell transplantation, in patients ...with advanced hematologic disease. The regimen consisted of fludarabine 25 mg/m2 per day for 5 days, melphalan 140 mg/m2 for one day, and TMLI radiation at 150 cGy/fraction in 8 fractions over 4 days. Eligible patients were over 50 years old and/or had compromised organ function. Median age of the 33 evaluable patients was 55.2 years. Eighteen events of nonhematologic grade III or higher toxicities occurred in 9 patients. Day 30 and day 100 mortalities were 3% and 15%, respectively. Patients achieved myeloid and platelet engraftment at a median of 14 days after transplantation. Long-term toxicities occurred in 2 patients: hypokalemia and tremor, both grade III, on days 370 and 361 after transplantation. Fourteen patients died, 7 of relapse-related causes and 7 of non–relapse-related causes. With a median follow-up for living patients of 14.7 months, 1-year overall survival, event-free survival, and non–relapse-related mortality were 75%, 65%, and 19%, respectively. Addition of TMLI to RIC is feasible and safe and could be offered to patients with advanced hematologic malignancies who might not otherwise be candidates for RIC.
There is a growing need to develop variant prediction tools capable of assessing a wide spectrum of evidence. We present a Bayesian framework that involves aggregating pathogenicity data across ...multiple in silico scores on a gene-by-gene basis and multiple evidence statistics in both quantitative and qualitative forms, and performs 5-tiered variant classification based on the resulting probability credible interval. When evaluated in 1,161 missense variants, our gene-specific in silico model-based meta-predictor yielded an area under the curve (AUC) of 96.0% and outperformed all other in silico predictors. Multifactorial model analysis incorporating all available evidence yielded 99.7% AUC, with 22.8% predicted as variants of uncertain significance (VUS). Use of only 3 auto-computed evidence statistics yielded 98.6% AUC with 56.0% predicted as VUS, which represented sufficient accuracy to rapidly assign a significant portion of VUS to clinically meaningful classifications. Collectively, our findings support the use of this framework to conduct large-scale variant prioritization using in silico predictors followed by variant prediction and classification with a high degree of predictive accuracy.
This article presents a six-rule algorithm for the reconstruction of multiple minimum-recombinant haplotype configurations in pedigrees. The algorithm has three major features: First, it allows ...exhaustive search of all possible haplotype configurations under the criterion that there are minimum recombinants between markers. Second, its computational requirement is on the order of O(J
2L
3) in current implementation, where
J is the family size and
L is the number of marker loci under analysis. Third, it applies to various pedigree structures, with and without consanguinity relationship, and allows missing alleles to be imputed, during the haplotyping process, from their identical-by-descent copies. Haplotyping examples are provided using both published and simulated data sets.
PDF
