Methods of integrating data to uncover genotype–phenotype interactions

Ritchie, Marylyn D.; Holzinger, Emily R.; Li, Ruowang; Pendergrass, Sarah A.; Kim, Dokyoon

doi:10.1038/nrg3868

Cited by 853 publications

(773 citation statements)

References 98 publications

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“…There are two main strategies for integration: multistage (stepwise or sequential) and meta-dimensional (simultaneous) analyses (Ritchie et al 2015). The multistage analyses are stepwise or hierarchical methods that rely on the central dogma of biology in which variations at the DNA level will hierarchically affect RNA levels, protein expression and so on.…”

Section: Multi-omics Data Integrationmentioning

confidence: 99%

“…By doing so, this methodology does not, however, provide statistics on the interactions betweenomics levels since they were treated separately. Statistical integration methods perform statistical association between biomolecules from different -omics levels (Cavill et al 2015;Ritchie et al 2015). The main statistical integration approaches can either be based on correlation, concatenation, multivariate or pathway analysis, which are further detailed in Table 1 along with suggestions of useful tools that implement each approach.…”

Section: Multi-omics Data Integrationmentioning

confidence: 99%

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Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

et al. 2015

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Worldwide population is aging, and a large part of the growing burden associated with age-related conditions can be prevented or delayed by promoting healthy lifestyle and normalizing metabolic risk factors. However, a better understanding of the pleiotropic effects of available nutritional interventions and their influence on the multiple processes affected by aging is needed to select and implement the most promising actions. New methods of analysis are required to tackle the complexity of the interplay between nutritional interventions and aging, and to make sense of a growing amount of -omics data being produced for this purpose. In this paper, we review how various systems biology-inspired methods of analysis can be applied to the study of the molecular basis of nutritional interventions promoting healthy aging, notably caloric restriction and polyphenol supplementation. We specifically focus on the role that different versions of network analysis, molecular signature identification and multiomics data integration are playing in elucidating the complex mechanisms underlying nutrition, and provide some examples on how to extend the application of these methods using available microarray data.

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Section: Multi-omics Data Integrationmentioning

confidence: 99%

Section: Multi-omics Data Integrationmentioning

confidence: 99%

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

et al. 2015

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“…In general, studies are incomparable limiting that capacity to integrate. Figure developed from concepts introduced in refs 113, 114…”

Section: Biology As a Systemmentioning

confidence: 99%

Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

Mueller

Peffers

Proctor³

et al. 2017

J. Orthop. Res.

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Systems orientated research offers the possibility of identifying novel therapeutic targets and relevant diagnostic markers for complex diseases such as osteoarthritis. This review demonstrates that the osteoarthritis research community has been slow to incorporate systems orientated approaches into research studies, although a number of key studies reveal novel insights into the regulatory mechanisms that contribute both to joint tissue homeostasis and its dysfunction. The review introduces both top‐down and bottom‐up approaches employed in the study of osteoarthritis. A holistic and multiscale approach, where clinical measurements may predict dysregulation and progression of joint degeneration, should be a key objective in future research. The review concludes with suggestions for further research and emerging trends not least of which is the coupled development of diagnostic tests and therapeutics as part of a concerted effort by the osteoarthritis research community to meet clinical needs. © 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1573–1588, 2017.

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“…The decoded output is being represented by the resulting phenotype (P ). Genetic textbook knowledge dictates that phenotypic responses result from the serial/hierarchical processing of the above mechanisms, as mE → G → E → T r → T l → P (Hypothesis A) [16]. Recently, an alternative hypothesis has been postulated that assumes all intracellular processing levels are interconnected implying a parallel cellular encoding (Hypothesis B) [16].…”

Section: Cc-by-nc-ndmentioning

confidence: 99%

On the principles of cell decision-making: intracellular coupling improves cell responses fidelity of noisy signals

Reppas

Jorswieck

Hatzikirou

2017

Preprint

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Reliability of cell fate decision-making is crucial to biological development. Until today it has not been clear what are biology's design principles that allow for reliable cell decision making under the influence of noise. Here, we attempt to answer this question by drawing an analogy between cell decision-making and information theory. We show that coupling of intracellular signalling pathway networks makes cell phenotypic responses reliable for noisy signals. As a proof of concept, we show how cis-interaction of the Notch-Delta pathway allows for increased performance under the influence of noise. Interestingly, in this case, the coupling principle leads to an efficient energy management. Finally, our postulated principle offers a compelling argument why cellular encoding is organized in a non-linear and non-hierarchical manner.Intoduction.− Cell decisions are responses of cell's internal mechanisms to external signals [1]. Such mechanisms are typically termed as signal transduction pathways. Signal transduction occurs when an extracellular signalling molecule bounds to a certain receptor creating a complex. In turn, this complex of molecules triggers a biochemical chain of events inside the cell, leading to a phenotypic response [2]. These responses are required to be of high fidelity and reliability since they are related to vital organism processes, such as cellular metabolism, shape, differentiation, or mitotic activity [3].Signal transduction pathways can be considered as input-output communication channels. Each pathway involves a number of key interacting proteins. The chain of biochemical events that involves the reception, endocytosis, activation/inactivation, nucleus internalisation, degradation or exocytosis of such a protein defines a single processing channel, in terms of encoding and decoding. The network of interactions of these coupled proteinchannels defines the signal transduction channel.Signal transduction pathways are subject to noisy perturbations. Typically, intracellular or intrinsic noise corresponds to thermal/stochastic fluctuations of the involved protein interactions. Alternatively, it may also account for any unknown and unobserved protein. Extrinsic noise lumps phenomena that contribute to stochasticity in cell-cell or cell-microenvironment communication.In this paper, we seek answers on biology's design principles that allow for reliable cell decision-making under the influence of noise. By means of a minimalistic communication model, we show that channel coupling can enhance the information capacity. In turn, we focus on dynamic cell fate determination processes, such as the Notch-Delta pathway, by establishing an analogy with communication theoretical concepts. We show that pathway coupling improves the reliability of responses in noisy * haralampos.hatzikirou@helmholtz-hzi.de environments which, thus, can be considered as a mechanism for robust cell-decision making.From information theory to cell decision-making.− Cells can be viewed as decision-makers that constantly proce...

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Methods of integrating data to uncover genotype–phenotype interactions

Cited by 853 publications

References 98 publications

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

On the principles of cell decision-making: intracellular coupling improves cell responses fidelity of noisy signals

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