Mittwoch, 20. September 2017

Computational disease modeling – fact or fiction?

Tegnér et al. (2009): Computational disease modeling - fact or fiction?

In the Abstract, we can learn about the two main approaches towards computational systems biology:
There are two conceptual traditions in biological computational-modeling. The bottom-up approach emphasizes complex intracellular molecular models and is well represented within the systems biology community. On the other hand, the physics-inspired top-down modeling strategy identifies and selects features of (presumably) essential relevance to the phenomena of interest and combines available data in models of modest complexity.
[T]he development of predictive hierarchical models spanning several scales beyond intracellular molecular networks was identified as a major objective. This contrasts with the current focus within the systems biology community on complex molecular modeling.
A couple of more quotes from the paper. First, about standards for data-collection and representation:
Successful modeling of diseases is greatly facilitated by standards for data-collection and storage, interoperable representation, and computational tools enabling pattern/network analysis and modeling. There are several important initiatives in this direction, such as the ELIXIR program providing sustainable bioinformatics infrastructure for biomedical data in Europe. Similar initiatives are in progress in the USA and Asia.
Next, about model uncertainty:
Across different application areas, a key question concerns the handling of model uncertainty. This refers to the fact that for any biological system there are numerous competing models. Any discursive model of a biological system therefore involves uncertainty and incompleteness. Computational model selection has to cope systematically with the fact that there could be additional relevant interactions and components beyond those that are represented in the discursive model. For instance, there is often insufficient experimental determination of kinetic values for mechanisms contemplated in a verbal model, leading to serious indetermination of parameters in a computational model. Hence, biological models, unlike models describing physical laws, are as a rule highly over-parameterized with respect to the available data. This means that different regions of the parameter space can describe the available data equally well from a statistical point-of-view.
A successful strategy in computational neuroscience has been to identify minimal models that adequately describe and predict the biology, but at the potential price of selecting a too narrowly focused model. This approach is justified if adequate knowledge of the underlying mechanisms involved in a given condition exists.
An alternative approach, recently employed within the systems biology and computational neuroscience fields, is to search for parameter dimensions (as opposed to individual parameter sets) that are important for model performance. This concept of model ensembles represents a promising approach.
[A] mechanistic model is not very helpful unless there are experimental means to assess its predictive validity[.]
How do systems biology and computational neuroscience differ?
It appears that the systems biology community focuses on intracellular networks whereas computational neuroscience emphasizes top-down modeling.
It must also be recognized that top-down models of insufficient richness may excessively constrain model space and lose predictive ability.
Further, the authors write about theory and formal models:
There is a lack of theory for how to integrate model selection with constraint propagation across several layers of biological organization. Development of such a theory could be useful in modeling complex diseases even when only sparse data is available. One useful practical first approximation is the notion of disease networks – i.e. network representations of shared attributes among different diseases and their (potential) molecular underpinnings.
[In computational systems biology], much attention is given to formal methods of model selection and datadriven model construction. In contrast, in computational neuroscience (with the notable exception of computational neuroimaging), formal model selection methods are almost completely absent.

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