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Personalized characterization of diseases using sample-specific networks.

ABSTRACT: A complex disease generally results not from malfunction of individual molecules but from dysfunction of the relevant system or network, which dynamically changes with time and conditions. Thus, estimating a condition-specific network from a single sample is crucial to elucidating the molecular mechanisms of complex diseases at the system level. However, there is currently no effective way to construct such an individual-specific network by expression profiling of a single sample because of the requirement of multiple samples for computing correlations. We developed here with a statistical method, i.e. a sample-specific network (SSN) method, which allows us to construct individual-specific networks based on molecular expressions of a single sample. Using this method, we can characterize various human diseases at a network level. In particular, such SSNs can lead to the identification of individual-specific disease modules as well as driver genes, even without gene sequencing information. Extensive analysis by using the Cancer Genome Atlas data not only demonstrated the effectiveness of the method, but also found new individual-specific driver genes and network patterns for various types of cancer. Biological experiments on drug resistance further validated one important advantage of our method over the traditional methods, i.e. we can even identify such drug resistance genes that actually have no clear differential expression between samples with and without the resistance, due to the additional network information.

SUBMITTER: Liu X

PROVIDER: S-EPMC5159538 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Personalized characterization of diseases using sample-specific networks.

Liu Xiaoping X Wang Yuetong Y Ji Hongbin H Aihara Kazuyuki K Chen Luonan L

Nucleic acids research 20160904 22

A complex disease generally results not from malfunction of individual molecules but from dysfunction of the relevant system or network, which dynamically changes with time and conditions. Thus, estimating a condition-specific network from a single sample is crucial to elucidating the molecular mechanisms of complex diseases at the system level. However, there is currently no effective way to construct such an individual-specific network by expression profiling of a single sample because of the ...[more]

PMID: 27596597

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Project description:PurposeFunctional-guided radiation therapy (RT) plans have the potential to limit damage to normal tissue and reduce toxicity. Although functional imaging modalities have continued to improve, a limited understanding of the functional response to radiation and its application to personalized therapy has hindered clinical implementation. The purpose of this study was to retrospectively model the longitudinal, patient-specific dose-function response in non-small cell lung cancer patients treated with RT to better characterize the expected functional damage in future, unknown patients.Methods and materialsPerfusion single-photon emission computed tomography/computed tomography scans were obtained at baseline (n = 81), midtreatment (n = 74), 3 months post-treatment (n = 51), and 1 year post-treatment (n = 26) and retrospectively analyzed. Patients were treated with conventionally fractionated RT or stereotactic body RT. Normalized perfusion single-photon emission computed tomography voxel intensity was used as a surrogate for local lung function. A patient-specific logistic model was applied to each individual patient's dose-function response to characterize functional reduction at each imaging time point. Patient-specific model parameters were averaged to create a population-level logistic dose-response model.ResultsA significant longitudinal decrease in lung function was observed after RT by analyzing the voxelwise change in normalized perfusion intensity. Generated dose-function response models represent the expected voxelwise reduction in function, and the associated uncertainty, for an unknown patient receiving conventionally fractionated RT or stereotactic body RT. Differential treatment responses based on the functional status of the voxel at baseline suggest that initially higher functioning voxels are damaged at a higher rate than lower functioning voxels.ConclusionsThis study modeled the patient-specific dose-function response in patients with non-small cell lung cancer during and after radiation treatment. The generated population-level dose-function response models were derived from individual patient assessment and have the potential to inform functional-guided treatment plans regarding the expected functional lung damage. This type of patient-specific modeling approach can be applied broadly to other functional response analyses to better capture intrapatient dependencies and characterize personalized functional damage.

Project description:Recent advances in large datasets analysis offer new insights to modern biology allowing system-level investigation of pathologies. Here we describe a novel computational method that exploits the ever-growing amount of "omics" data to shed light on Alzheimer's and Parkinson's diseases. Neurological disorders exhibit a huge number of molecular alterations due to a complex interplay between genetic and environmental factors. Classical reductionist approaches are focused on a few elements, providing a narrow overview of the etiopathogenic complexity of multifactorial diseases. On the other hand, high-throughput technologies allow the evaluation of many components of biological systems and their behaviors. Analysis of Parkinson's Disease (PD) and Alzheimer's Disease (AD) from a network perspective can highlight proteins or pathways common but differently represented that can be discriminating between the two pathological conditions, thus highlight similarities and differences.In this work we propose a strategy that exploits network community structure identified with a state-of-the-art network community discovery algorithm called InfoMap, which takes advantage of information theory principles. We used two similarity measurements to quantify functional and topological similarities between the two pathologies. We built a Similarity Matrix to highlight similar communities and we analyzed statistically significant GO terms found in clustered areas of the matrix and in network communities. Our strategy allowed us to identify common known and unknown processes including DNA repair, RNA metabolism and glucose metabolism not detected with simple GO enrichment analysis. In particular, we were able to capture the connection between mitochondrial dysfunction and metabolism (glucose and glutamate/glutamine).This approach allows the identification of communities present in both pathologies which highlight common biological processes. Conversely, the identification of communities without any counterpart can be used to investigate processes that are characteristic of only one of the two pathologies. In general, the same strategy can be applied to compare any pair of biological networks.

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Personalized characterization of diseases using sample-specific networks.

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Personalized characterization of diseases using sample-specific networks.

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