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Airoldi, Edoardo

We live in an increasingly mobile world, which leads to the duplication of information across domains. Though organizations attempt to obscure the identities of their constituents when sharing information for worthwhile purposes, such as basic research, the uncoordinated nature of such environment can lead to privacy vulnerabilities. For instance, disparate healthcare providers can collect information on the same patient. Federal policy requires that such providers share “de-identified” sensitive data, such as biomedical (e.g., clinical and genomic) records. But at the same time, such providers can share identified information, devoid of sensitive biomedical data, for administrative functions. On a provider-by-provider basis, the biomedical and identified records appear unrelated, however, links can be established when multiple providers' databases are studied jointly. The problem, known as trail disclosure, is a generalized phenomenon and occurs because an individual's location access pattern can be matched across the shared databases. Due to technical and legal constraints, it is often difficult to coordinate between providers and thus it is critical to assess the disclosure risk in distributed environments, so that we can develop techniques to mitigate such risks. Research on privacy protection has so far focused on developing technologies to suppress or encrypt identifiers associated with sensitive information. There is a growing body of work on the formal assessment of the disclosure risk of database entries in publicly shared databases, but less attention has been paid to the distributed setting. In this research, we review the trail disclosure problem in several domains with known vulnerabilities and show that disclosure risk is influenced by the distribution of how people visit service providers. Based on empirical evidence, we propose an entropy metric for assessing such risk in shared databases prior to their release. This metric assesses risk by leveraging the statistical characteristics of a visit distribution, as opposed to person-level data. It is computationally efficient and superior to existing risk assessment methods, which rely on ad hoc assessment that are often computationally expensive and unreliable. We evaluate our approach on a range of location access patterns in simulated environments. Our results demonstrate that the approach is effective at estimating trail disclosure risks and the amount of self- information contained in a distributed system is one of the main driving factors.

Molecular regulation of embryonic stem cell (ESC) fate involves a coordinated interaction between epigenetic, transcriptional and translational mechanisms. It is unclear how these different molecular regulatory mechanisms interact to regulate changes in stem cell fate. Here we present a dynamic systems-level study of cell fate change in murine ESCs following a well-defined perturbation. Global changes in histone acetylation, chromatin-bound RNA polymerase II, messenger RNA (mRNA), and nuclear protein levels were measured over 5 days after downregulation of Nanog, a key pluripotency regulator. Our data demonstrate how a single genetic perturbation leads to progressive widespread changes in several molecular regulatory layers, and provide a dynamic view of information flow in the epigenome, transcriptome and proteome. We observe that a large proportion of changes in nuclear protein levels are not accompanied by concordant changes in the expression of corresponding mRNAs, indicating important roles for translational and post-translational regulation of ESC fate. Gene-ontology analysis across different molecular layers indicates that although chromatin reconfiguration is important for altering cell fate, it is preceded by transcription-factor-mediated regulatory events. The temporal order of gene expression alterations shows the order of the regulatory network reconfiguration and offers further insight into the gene regulatory network. Our studies extend the conventional systems biology approach to include many molecular species, regulatory layers and temporal series, and underscore the complexity of the multi-layer regulatory mechanisms responsible for changes in protein expression that determine stem cell fate.

Methods for generating a random sample of networks with desired properties are important tools for the analysis of social, biological, and information networks. Algorithm-based approaches to sampling networks have received a great deal of attention in recent literature. Most of these algorithms are based on simple intuitions that associate the full features of connectivity patterns with specific values of only one or two network metrics. Substantive conclusions are crucially dependent on this association holding true. However, the extent to which this simple intuition holds true is not yet known. In this paper, we examine the association between the connectivity patterns that a network sampling algorithm aims to generate and the connectivity patterns of the generated networks, measured by an existing set of popular network metrics. We find that different network sampling algorithms can yield networks with similar connectivity patterns. We also find that the alternative algorithms for the same connectivity pattern can yield networks with different connectivity patterns. We argue that conclusions based on simulated network studies must focus on the full features of the connectivity patterns of a network instead of on the limited set of network metrics for a specific network type. This fact has important implications for network data analysis: for instance, implications related to the way significance is currently assessed.

Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in a concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step toward dissecting the multilayer regulatory mechanisms that determine stem cell fate.

In a communication network, point-to-point traffic volumes over time are critical for designing protocols that route information efficiently and for maintaining security, whether at the scale of an Internet service provider or within a corporation. While technically feasible, the direct measurement of point-to-point traffic imposes a heavy burden on network performance and is typically not implemented. Instead, indirect aggregate traffic volumes are routinely collected. We consider the problem of estimating point-to-point traffic volumes, (x_t), from aggregate traffic volumes, (y_t), given information about the network routing protocol encoded in a matrix A. This estimation task can be reformulated as finding the solutions to a sequence of ill-posed linear inverse problems, (y_t=Ax_t), since the number of origin-destination routes of interest is higher than the number of aggregate measurements available. Here, we introduce a novel multilevel state-space model (SSM) of aggregate traffic volumes with realistic features. We implement a naïve strategy for estimating unobserved point-to-point traffic volumes from indirect measurements of aggregate traffic, based on particle filtering. We then develop a more efficient two-stage inference strategy that relies on model-based regularization: a simple model is used to calibrate regularization parameters that lead to efficient/scalable inference in the multilevel SSM. We apply our methods to corporate and academic networks, where we show that the proposed inference strategy outperforms existing approaches and scales to larger networks. We also design a simulation study to explore the factors that influence the performance. Our results suggest that model-based regularization may be an efficient strategy for inference in other complex multilevel models. Supplementary materials for this article are available online.

Countless studies monitor the growth rate of microbial populations as a measure of fitness. However, an enormous gap separates growth-rate differences measurable in the laboratory from those that natural selection can distinguish efficiently. Taking advantage of the recent discovery that transcript and protein levels in budding yeast closely track growth rate, we explore the possibility that growth rate can be more sensitively inferred by monitoring the proteomic response to growth, rather than growth itself. We find a set of proteins whose levels, in aggregate, enable prediction of growth rate to a higher precision than direct measurements. However, we find little overlap between these proteins and those that closely track growth rate in other studies. These results suggest that, in yeast, the pathways that set the pace of cell division can differ depending on the growth-altering stimulus. Still, with proper validation, protein measurements can provide high-precision growth estimates that allow extension of phenotypic growth-based assays closer to the limits of evolutionary selection.

The goal of dimensionality reduction is to embed high-dimensional data in a low-dimensional space while preserving structure in the data relevant to exploratory data analysis such as clusters. However, existing dimensionality reduction methods often either fail to separate clusters due to the crowding problem or can only separate clusters at a single resolution. We develop a new approach to dimensionality reduction: tree preserving embedding. Our approach uses the topological notion of connectedness to separate clusters at all resolutions. We provide a formal guarantee of cluster separation for our approach that holds for finite samples. Our approach requires no parameters and can handle general types of data, making it easy to use in practice and suggesting new strategies for robust data visualization.

The respiratory metabolic cycle in budding yeast (Saccharomyces cerevisiae) consists of two phases most simply defined phenomenologically: low oxygen consumption (LOC) and high oxygen consumption (HOC). Each phase is associated with the periodic expression of thousands of genes, producing oscillating patterns of gene-expression found in synchronized cultures and in single cells of slowly growing unsynchronized cultures. Systematic variation in the durations of the HOC and LOC phases can account quantitatively for well-studied transcriptional responses to growth rate differences. Here we show that a similar mechanism, transitions from the HOC phase to the LOC phase, can account for much of the common environmental stress response (ESR) and for the cross protection by a preliminary heat stress (or slow growth rate) to subsequent lethal heat-stress. Similar to the budding yeast metabolic cycle, we suggest that a metabolic cycle, coupled in a similar way to the ESR, in the distantly related fission yeast, Schizosaccharomyces pombe, and in human can explain gene-expression and respiratory patterns observed in these organisms. Although metabolic cycling is associated with the G0/G1 phase of the cell division cycle of slowly growing budding yeast, transcriptional cycling was detected in the G2 phase of the division cycle in fission yeast, consistent with the idea that respiratory metabolic cycling occurs during the phases of the cell division cycle associated with mass accumulation in these divergent eukaryotes.

In his campaign for the U.S. presidency from 1975 to 1979, Ronald Reagan delivered over 1000 radio broadcasts. For over 600 of these we have direct evidence of Reagan's authorship. The aim of this study was to determine the authorship of 312 of the broadcasts for which no direct evidence is available. We addressed the prediction problem for speeches delivered in different epochs and we explored a wide range of off-the-shelf classification methods and fully Bayesian generative models. Eventually we produced separate sets of predictions using the most accurate classifiers, based on non-contextual words as well as on semantic features, for the 312 speeches of uncertain authorship. All the predictions agree on 135 of the "unknown" speeches, whereas the fully Bayesian models agree on an additional 154 of them.

The magnitude of the posterior odds of authorship led us to conclude that Ronald Reagan drafted 167 speeches and was aided in the preparation of the remaining 145. Our inferences were not sensitive to "reasonable" variations in the sets of constants underlying the prior distributions, and the cross-validated accuracy of our best fully Bayesian model was above 90 percent in all cases. The agreement of multiple methods for predicting the authorship for the "unknown" speeches reinforced our confidence in the accuracy of our classifications.

Fermenting glucose in the presence of enough oxygen to support respiration, known as aerobic glycolysis, is believed to maximize growth rate. We observed increasing aerobic glycolysis during exponential growth, suggesting additional physiological roles for aerobic glycolysis. We investigated such roles in yeast batch cultures by quantifying (O_2) consumption, (CO_2) production, amino acids, mRNAs, proteins, posttranslational modifications, and stress sensitivity in the course of nine doublings at constant rate. During this course, the cells support a constant biomass-production rate with decreasing rates of respiration and ATP production but also decrease their stress resistance. As the respiration rate decreases, so do the levels of enzymes catalyzing rate-determining reactions of the tricarboxylic-acid cycle (providing NADH for respiration) and of mitochondrial folate-mediated NADPH production (required for oxidative defense). The findings demonstrate that exponential growth can represent not a single metabolic/physiological state but a continuum of changing states and that aerobic glycolysis can reduce the energy demands associated with respiratory metabolism and stress survival.