ASKE Month 6 Milestone Report

Making model analysis and model content fully auditable

When browsing the results of model tests, it is often of interest to inspect the specific provenance of each modeled mechanisms that contributed to the result. EMMAA models are built automatically from primary knowledge sources (databases and literature), and model components are annotated such that given the result, we can link back to the original sources.

Links to browse evidence are available in all of the following contexts:

  • New statements added to the model

  • Most supported statements in the model

  • New tests applicable to the model

  • Passed/failed tests and the mechanisms constituting paths by which tests passed

../_images/akt_mtor_linkout.png ../_images/akt_mtor_curation.png

Including new information based on relevance

EMMAA models self-update by searching relevant litearture each day and adding mechanisms described in new publications. However, event publications that are relevant often contain pieces of information that aren’t directly relevant for the model. We therefore created a relevance filter which can take one of several policies and determine if a new statement is relevant to the given model or not. The strictest policy is called prior_all which only considers statements in which all participants are prior search terms of interest for the model as relevant. A less strict policy, prior_one requires that at least one participant of a statement is a prior search term for the model. Currently, EMMAA models are running with the prior_one policy.

Coarse-grained model checking of EMMAA models with directed graphs

To determine whether a model can satisfy a particular test, EMMAA currently assembles sets of INDRA Statements into mechanistic PySB/Kappa models. The INDRA ModelChecker is then used to determine whether there is a causal path in the Kappa influence map linking the subject and object of the test with the appropriate causal constraints. These constraints include the polarity of the path, the detailed attributes of the subject and object (for example, a particular modified form of the object protein), and the type of regulation (e.g., regulation of activity vs. regulation of amount). Because the assembled PySB/Kappa models make maximum use of available mechanistic information, this approach to model checking yields results with high precision, in that the existence of a path indicates that the strict semantics of the test are satisfied.

The high precision of this approach comes at the expense of recall and robustness, in that tests may not pass due to subtle aspects of the test or model statements. For example, if a machine reading system incorrectly extracts a positive regulation statement linking genes A and B as a regulation of amount rather than a regulation of activity, this can lead to the test “A activates B” failing and yielding no paths.

To help scientists using EMMAA to generate scientific insight, it would be ideal for models to be verified against tests with different degrees of causal constraints. If a model fails to satisfy a test using the high-precision approach, the scientist user could also inspect causal paths produced by model assembly and checking procedures with a more generous interpretation of causality.

A key advantage of using INDRA as the model assembly engine within EMMAA is that a single knowledge representation (INDRA Statements) can be used to assemble multiple types of causal models. In the context of EMMAA, INDRA can be used to assemble at least four different types of models, listed in increasing order of causal precision:

  • Directed networks

  • Signed directed networks

  • Boolean networks

  • Biological Expression Language (BEL) networks

  • PySB model/Kappa influence maps

During this reporting period, we investigated the use of the most coarse-grained of these representations, directed networks, to check EMMAA models against tests. Code and results are available in an iPython notebook accompanying this report available on Github here. Using the most recent model and test results from the EMMAA Ras Machine 2.0, we built a simple directed graph among agents using networkx and checked for paths between pairs of genes in the applied tests.

We found that, as expected, many more tests passed in the directed graph model (509 tests, 58.7%) than the detailed PySB/Kappa model (165 tests, 19.0%). All tests passed by the PySB/Kappa model also passed in the directed graph model, indicating that the latter is a strict subset of the former. Roughly half (52%) of the tests that failed in the PySB/Kappa model yielded paths in the directed graph. Inspection of the discrepancies highlighted some characteristics of these types of tests (see iPython notebook.) A key point is that the proportion of tests passed by the directed graph model represent an upper bound of the mechanistic coverage of the model that is independent of the particular modeling formalism involved. While many of the paths found in the directed graph do not satisfy the strictest interpretation of the tests, they are nevertheless useful for a human scientist to better understand relevant processes contained in the model and to generate hypotheses.

In the upcoming reporting period we aim to extend this approach further by using EMMAA to assemble multiple types of models at different levels of causal resolution. A scientist will then be able to explore a range of explanations for a given observation depending on the precision-recall tradeoffs of their use case.