Marco Ramoni's research while affiliated with Boston Children's Hospital and other places

Publications (193)

Article
Bayesian Belief Networks (BBNs) are a powerful formalism for reasoning under uncertainty but bear some severe limitations: they require a large amount of information before any reasoning process can start, they have limited contradiction handling capabilities, and their ability to provide explanations for their conclusion is still controversial. Th...
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Bayesian approaches to learn the graphical structure of Bayesian Belief Networks (BBNs) from databases share the assumption that the database is complete, that is, no entry is reported as unknown. Attempts to relax this assumption involve the use of expensive iterative methods to discriminate among different structures. This paper introduces a dete...
Article
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This paper describes a decision theoretic formulation of learning the graphical structure of a Bayesian Belief Network from data. This framework subsumes the standard Bayesian approach of choosing the model with the largest posterior probability as the solution of a decision problem with a 0-1 loss function and allows the use of more general loss f...
Data
Table of maximum AUCs. These are the maximum AUCs corresponding to Figure 2 for all values of prevalence. Row names represent values of heritability (computed on the observed binary scale) or proportion of phenotypic variance explained, and column names represent values of prevalence.
Data
Table of maximum sensitivities for each specificity. Rows represent the combination of heritability (H.sq, computed on the observed binary scale) and prevalence (Prev), while columns represent specificities. The elements are the maximal sensitivity in each case.
Data
Archive containing instructions (readme.txt) and computer code (maxAcc.r) to implement our algorithms. The code is written in the free statistical language and environment R (http://www.r-project.org), relies on free R optimization packages, and is copyrighted by the permissive MIT license (http://www.opensource.org/licenses/mit-license.html). Upda...
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Background Pre-symptomatic prediction of disease and drug response based on genetic testing is a critical component of personalized medicine. Previous work has demonstrated that the predictive capacity of genetic testing is constrained by the heritability and prevalence of the tested trait, although these constraints have only been approximated und...
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HIV-1-infected individuals with higher viral set points progress to AIDS more rapidly than those with lower set points. Predicting viral set point early following infection can contribute to our understanding of early control of HIV-1 replication, to predicting long-term clinical outcomes, and to the choice of optimal therapeutic regimens. In a lon...
Article
Abilities to successfully quit smoking display substantial evidence for heritability in classic and molecular genetic studies. Genome-wide association (GWA) studies have demonstrated single-nucleotide polymorphisms (SNPs) and haplotypes that distinguish successful quitters from individuals who were unable to quit smoking in clinical trial participa...
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We introduce a principled computational framework and methodology for automated discovery of context-specific functional links between ontologies. Our model leverages over disparate free-text literature resources to score the model of dependency linking two terms under a context against their model of independence. We identify linked terms as those...
Article
Inferring gene networks from longitudinal gene expression microarrays is a crucial step towards the study of gene regulatory mechanisms. A decade ago, expensive microarray technology restricted the number of samples undergoing gene expression profiling in single studies, leading the inference algorithms that assume stationary gene networks to the b...
Article
Smooth muscle cells (SMCs) have a pivotal role in cardiovascular diseases and are responsible for hyaluronan (HA) deposition in thickening vessel walls. HA regulates SMC proliferation, migration, and inflammation, which accelerates neointima formation. We used the HA synthesis inhibitor 4-methylumbelliferone (4-MU) to reduce HA production in human...
Article
Gene expression and genome wide association data have provided researchers the opportunity to study many complex traits and diseases. When designing prognostic and predictive models capable of phenotypic classification in this area, significant reduction of dimensionality through stringent filtering and/or feature selection is often deemed imperati...
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Full-text available
Smooth muscle cells (SMCs) have a pivotal role in cardiovascular diseases and are responsible for hyaluronan (HA) deposition in thickening vessel walls. HA regulates SMC proliferation, migration, and inflammation, which accelerates neointima formation. We used the HA synthesis inhibitor 4-methylumbelliferone (4-MU) to reduce HA production in human...
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Full-text available
Synthetic biology is the new frontier of biological engineering. Instead of incrementally altering living organisms, synthetic biologists propose to use biological knowledge, modular biological parts, and computer-aided design to quickly develop systems capable of unprecedented biochemical feats. Synthetic biology therefore promises dramatic
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Feedback control is an important regulatory process in biological systems, which confers robustness against external and internal disturbances. Genes involved in feedback structures are therefore likely to have a major role in regulating cellular processes. Here we rely on a dynamic Bayesian network approach to identify feedback loops in cell cycle...
Article
Transcriptional networks play a central role in cancer development. The authors described a systems biology approach to cancer classification based on the reverse engineering of the transcriptional network surrounding the 2 most common types of lung cancer: adenocarcinoma (AC) and squamous cell carcinoma (SCC). A transcriptional network classifier...
Article
The following sections are included: Introduction, Session Papers, Acknowledgments and References.
Article
The etiology of growth impairment in Crohn's disease (CD) has been inadequately explained by nutritional, hormonal, and/or disease-related factors, suggesting that genetics may be an additional contributor. The aim of this cross-sectional study was to investigate genetic variants associated with linear growth in pediatric-onset CD. We genotyped 951...
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Identification of expression quantitative trait loci (eQTLs) is an emerging area in genomic study. The task requires an integrated analysis of genome-wide single nucleotide polymorphism (SNP) data and gene expression data, raising a new computational challenge due to the tremendous size of data. We develop a method to identify eQTLs. The method rep...
Article
Reverse-engineering transcriptional networks from longitudinal expression profiles is a crucial step towards the study of gene regulatory mechanisms. Genes dynamically orchestrate to each other, the stationarity assumption made by existing methods of transcriptional interaction inference is no longer adequate. As such, we need a new approach to han...
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Vibrio cholerae is a Gram-negative bacillus that is the causative agent of cholera. Pathogenesis in vivo occurs through a series of spatiotemporally controlled events under the control of a gene cascade termed the ToxR regulon. Major genes in the ToxR regulon include the master regulators toxRS and tcpPH, the downstream regulator toxT, and virulenc...
Chapter
Bayesian networks are today one of the most promising approaches to Data Mining and knowledge discovery in databases. This chapter reviews the fundamental aspects of Bayesian networks and some of their technical aspects, with a particular emphasis on the methods to induce Bayesian networks from different types of data. Basic notions are illustrated...
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The Wilms' tumor suppressor 1 (WT1) gene encodes a DNA- and RNA-binding protein that plays an essential role in nephron progenitor differentiation during renal development. To identify WT1 target genes that might regulate nephron progenitor differentiation in vivo, we performed chromatin immunoprecipitation (ChIP) coupled to mouse promoter microarr...
Article
Objective: Identify clinical factors that modulate the risk of progression to COPD among asthma patients using data extracted from electronic medical records. Design: Demographic information and comorbidities from adult asthma patients who were observed for at least 5 years with initial observation dates between 1988 and 1998, were extracted from...
Conference Paper
Objectives: Tobacco use is a leading contributor to worldwide death and disability, and it is known that genetic factors play a role in the development of nicotine dependence (ND). While many studies have considered the association of individual single nucleotide polymorphisms (SNPs) with this complex trait, studies have not focused on creating pre...
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Information theory--a field at the intersection of applied mathematics and electrical engineering--was primarily developed for the purpose of addressing problems arising in data storage and data transmission over (noisy) communication media. Consequently, information theory provides the formal basis for much of today’s storage and communication inf...
Article
Many different genetic and clinical factors have been identified as causes or contributors to atherosclerosis. We present a model of preclinical atherosclerosis based on genetic and clinical data that predicts the presence of coronary artery calcification in healthy Americans of European descent 45 to 84 years of age in the Multi-Ethnic Study of At...
Article
The field of synthetic biology holds an inspiring vision for the future; it integrates computational analysis, biological data and the systems engineering paradigm in the design of new biological machines and systems. These biological machines are built from basic biomolecular components analogous to electrical devices, and the information flow amo...
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Like all primary cells in vitro, normal human melanocytes exhibit a physiologic decay in proliferative potential as it transitions to a growth-arrested state. The underlying transcriptional program(s) that regulate this phenotypic change is largely unknown. To identify molecular determinants of this process, we performed a Bayesian-based dynamic ge...
Article
Although the measurement of fetal proteins in maternal serum is part of standard prenatal screening for aneuploidy and neural tube defects, attempts to better understand the extent of feto-maternal protein trafficking and its clinical and biological significance have been hindered by the presence of abundant maternal proteins. The objective of this...
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Gene interactions play a central role in transcriptional networks. Many studies have performed genome-wide expression analysis to reconstruct regulatory networks to investigate disease processes. Since biological processes are outcomes of regulatory gene interactions, this paper develops a system biology approach to infer function-dependent transcr...
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Bronchodilator response tests measure the effect of beta(2)-agonists, the most commonly used short-acting reliever drugs for asthma. We sought to relate candidate gene SNP data with bronchodilator response and measure the predictive accuracy of a model constructed with genetic variants. Bayesian networks, multivariate models that are able to accoun...
Article
To summarize the available evidence on cooccurring gastrointestinal toxicities and their potential link with other symptoms in cancer patients. The information obtained from colorectal cancer patient cohorts will be used as an example. In recent years, it has become clear that gastrointestinal toxicities do not occur in isolation in cancer patients...
Conference Paper
This paper develops a Bayesian network (BN) predictor to profile cross-race gene expression data. Cross-race studies face more data variability than single-lab studies. Our design handles this problem by using the BN framework. In addition, unlike existing methods that unrealistically assume independent genes, our BN approach can capture the depend...
Article
Identify clinical factors that modulate the risk of progression to COPD among asthma patients using data extracted from electronic medical records. Demographic information and comorbidities from adult asthma patients who were observed for at least 5 years with initial observation dates between 1988 and 1998, were extracted from electronic medical r...
Article
Cardioembolic stroke is a complex disease resulting from the interaction of numerous factors. Using data from Genes Affecting Stroke Risk and Outcome Study (GASROS), we show that a multivariate predictive model built using Bayesian networks is able to achieve a predictive accuracy of 86% on the fitted values as computed by the area under the receiv...
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Individuals' dependence on nicotine, primarily through cigarette smoking, is a major source of morbidity and mortality worldwide. Many smokers attempt but fail to quit smoking, motivating researchers to identify the origins of this dependence. Because of the known heritability of nicotine-dependence phenotypes, considerable interest has been focuse...
Article
Surface-enhanced laser desorption/ionization time- of-flight mass spectrometry (SELDI or SELDI-TOF MS) has yielded predictive protein profiles for a number of clinically relevant diseases. Yet, rather than identifying specific proteins, such studies have provided diagnostic information solely based on "black box" predictors that look at differentia...
Article
Though genome-wide technologies, such as microarrays, are widely used, data from these methods are considered noisy; there is still varied success in downstream biological validation. We report a method that increases the likelihood of successfully validating microarray findings using real time RT-PCR, including genes at low expression levels and w...
Article
Unlabelled: Many bioinformatics solutions suffer from the lack of usable interface/platform from which results can be analyzed and visualized. Overcoming this hurdle would allow for more widespread dissemination of bioinformatics algorithms within the biological and medical communities. The algorithms should be accessible without extensive technic...
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The increasing availability of electronic medical records offers opportunities to better characterize patient populations and create predictive tools to individualize health care. We determined which asthma patients suffer exacerbations using data extracted from electronic medical records of the Partners Healthcare System using Natural Language Pro...
Article
The identification of reliable peripheral biomarkers for clinical diagnosis, patient prognosis, and biological functional studies would allow for access to biological information currently available only through invasive methods. Traditional approaches have so far considered aspects of tissues and biofluid markers independently. Here we introduce a...
Article
Colorectal cancer patients undergoing chemotherapy (CT) are likely to experience multiple concurrent toxicities that, rather than appearing singularly, may be associated with one another. Graphic and tabular representations of distance matrices were used to identify associations between toxicities and to define the strengths of these relations. Usi...
Chapter
Born at the intersection of artificial intelligence, statistics, and probability, Bayesian networks (Pearl, 1988) are a representation formalism at the cutting edge of knowledge discovery and data mining (Heckerman, 1997). Bayesian networks belong to a more general class of models called probabilistic graphical models (Whittaker, 1990; Lauritzen, 1...
Conference Paper
The accumulation of genomic and proteomic data of many organisms presents an opportunity to analyze entire phylogenetic trees in a systematic, quantified manner. The universal tree of life, constructed by genomic data, provides an evolutionary context for proteomic data of individual organisms. Using proteomic information mapped to biological funct...
Conference Paper
With the human genome sequenced, attention has been shifting to proteins and their function. Several technologies including mass spectrometry and gel electrophoresis have traditionally been used to study proteins. These technologies rely on proteins' masses to characterize and/or identify them. Once identified, the discovered proteins' are often an...
Article
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The discovery of fetal mRNA transcripts in the maternal circulation holds great promise for noninvasive prenatal diagnosis. To identify potential fetal biomarkers, we studied whole blood and plasma gene transcripts that were common to 9 term pregnant women and their newborns but absent or reduced in the mothers postpartum. RNA was isolated from per...
Conference Paper
The accumulation of genomic and proteomic data of many organisms presents an opportunity to analyze entire phylogenetic trees in a systematic, quantified manner. The Universal Tree of Life, constructed by genomic data, provides an evolutionary context for proteomic data of individual organisms. Using proteomic information mapped to biological funct...
Article
To evaluate the economic impact of a Bayesian network model designed to predict clinical success of a new chemical entity (NCE) based on pre-phase III data. We trained our Bayesian network model on publicly accessible data on 503 NCEs, stratified by therapeutic class. We evaluated the sensitivity, specificity and accuracy of our model on an indepen...
Article
Biological and medical data have been growing exponentially over the past several years [1, 2]. In particular, proteomics has seen automation dramatically change the rate at which data are generated [3]. Analysis that systemically incorporates prior information is becoming essential to making inferences about the myriad, complex data [4-6]. A Bayes...
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Paediatric drug development faces unique challenges because of two opposing concerns. On the one hand, the fundamental differences between growing and developing children and adults, such as different drug response and toxicity profiles and differences in rates of drug metabolism, require specific clinical trials to ascertain the safety and efficac...
Article
9045 Background: CRC patients undergoing CT are likely to experience multiple concurrent toxicities. Rather than appearing singularly, the hypothesis that certain toxicities occur in clusters may suggest a common pathobiology. We used Markov networks (MN), a probabilistic graphical born at the confluence of statistics and artificial intelligence de...
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The cardiovascular restricted transcription factor CHF1/Hey2 has been previously shown to regulate the smooth muscle response to growth factors. To determine how CHF1/Hey2 affects the smooth muscle response to growth factors, we performed a genomic screen for transcripts that are differentially expressed in wild-type and knockout smooth muscle cell...
Article
Unlabelled: Patients treated with radiotherapy are prone to a constellation of local and systemic toxicities including mucositis, xerostomia, fatigue and anorexia. The biological complexities and similarities underlying the development of toxicities have recently been realized. Mucosal barrier injury is one of the best studied, and gene expression...
Article
Velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome, now collectively referred to as 22q11deletion syndrome (22q11DS) are caused by microdeletions on chromosome 22q11. The great majority ( approximately 90%) of these deletions are 3 Mb in size. The remaining deleted patients have nested break-points resulting in over...
Article
Immunosuppressive drugs can be completely withdrawn in up to 20% of liver transplant recipients, commonly referred to as 'operationally' tolerant. Immune characterization of these patients, however, has not been performed in detail, and we lack tests capable of identifying tolerant patients among recipients receiving maintenance immunosuppression....
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The cost of developing an innovative drug remains the subject of ongoing debate, with some estimates now exceeding the widely quoted figure of US$802 million¹. Whatever the true cost, however, it is clear that late-stage clinical failures account for a large proportion of the expenses.
Article
There is a growing need for engineers in the burgeoning fields of bioinformatics and proteomics. The high-throughput nature of both of these related fields has made traditional biological methods, which tend to focus on one or two molecules at a time, obsolete. The consequent deluge of experiment-based information has made engineering and problem-s...
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Myelodysplastic syndromes (MDS) are among the most frequent hematologic malignancies. Patients have a short survival and often progress to acute myeloid leukemia. The diagnosis of MDS can be difficult; there is a paucity of molecular markers, and the pathophysiology is largely unknown. Therefore, we conducted a multicenter study investigating wheth...
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Reverse engineering cellular networks is currently one of the most challenging problems in systems biology. Dynamic Bayesian networks (DBNs) seem to be particularly suitable for inferring relationships between cellular variables from the analysis of time series measurements of mRNA or protein concentrations. As evaluating inference results on a rea...
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Recent studies have shown that when individuals are grouped on the basis of genetic similarity, group membership corresponds closely to continental origin. There has been considerable debate about the implications of these findings in the context of larger debates about race and the extent of genetic variation between groups. Some have argued that...