Computational Challenge – Crowdsourcing Systems Toxicology
The aim of this sbv IMPROVER challenge is to verify that robust and sparse human-specific or species-independent gene signatures predictive of smoking exposure or cessation status can be extracted from whole blood gene expression data from human, or human and rodent. The participants are asked to develop inductive (e.g., the signature model can be applied to a single new sample without retraining) rather than transductive (e.g., training and test set processed together and used to retrain models prior to classification prediction) models including identified gene signatures, to classify subjects as smoker versus non-current smoker, and in a second step, to discriminate non-current smoker as former smoker versus never smoker. Data that include metadata information are provided by challenge organizers for training. The participants have the freedom to use additional public blood-related gene expression data as training set(s). The participants will apply their trained signature models (classifiers) on new unrelated and unseen test datasets and will predict the class for each individual subject with a confidence level.
Humans are constantly exposed to individual or mixtures of chemicals (e.g., cigarette smoke, pollutants, pesticides, drugs) that may trigger molecular changes (e.g., gene expression) in their cells. The identification of specific markers of response to those chemicals is important to assess the exposure status of a subject. A subset of exogenous chemicals, chemical-derived metabolites, and endogenous molecules produced by exposed organs (e.g., lung, gut) can pass into the blood stream and induce molecular changes in blood cells, which for a subset can constitute a specific exposure response fingerprint or signature discriminating exposed vs. non-exposed subjects, and also formerly exposed vs never exposed subjects. Whole blood is an easily accessible matrix, but is a complex biofluid/tissue to analyze because of the different cell sub-populations that it contains.
Therefore, the new proposed computational challenge titled “Markers of Exposure Response Identification” articulates scientific questions around this problem.
Systems toxicology or 21st century toxicology, aims to create detailed understanding of the mechanisms by which biological systems respond to toxicants, so that this understanding can be leveraged to assess the risk of chemicals, drugs, and consumer products.
Fig 1: Systems toxicology aims to extrapolate short-term observations to long-term outcomes, and translate the potential risks identified from experimental systems to humans.
Toxicity testing is at a turning point now that long-range strategic planning is in progress to update and improve testing procedures for potential stressors.
The U.S. EPA has commissioned the National Research Council to develop a vision for toxicity testing in the 21st century (Tox 21-c) to base the new toxicology primarily on pathways of toxicity (PoT).
The report by the U.S. National Research Council (NRC) envisions a shift away from traditional toxicity testing and toward a focused effort to explore and understand the signaling pathways perturbed by biologically active substances or their metabolites that have the potential to cause adverse health effects in humans:
- to achieve testing of broad coverage of chemicals, mixtures, outcomes and life stages;
- to significantly increase human relevance;
- to reduce the cost and time required to conduct chemical safety assessments;
- to reduce and potentially eliminate high-dose animal testing.
The identification of these toxicity pathways is imperative in order to understand the mode of action (MOA) of a given stimulus and for grouping together different stimuli based on the toxicity pathways they perturb.
The first component of the vision focuses on pathway identification, which is preferably derived from studies performed in human cells or cell lines using omics assays. The second component of the vision involves targeted testing of the identified pathways in whole animals and clinical samples to further explain toxicity pathway data. This two-component toxicity-testing paradigm, combined with chemical characterization and dose–response extrapolation, delivers a much broader understanding of the potential toxicity associated with a biologically active substance.
Systems biology plays an important role in this paradigm, consolidating large amounts of information that can be probed to reveal key cellular pathways perturbed by various stimuli.
Fig 2: Integrating classical toxicology with quantitative analysis of the molecular and functional changes induced by toxicants, systems toxicology relies on the latest technological developments in both experimental and computational sciences.
Modified from Sturla, S. J. et al. Systems Toxicology: From Basic Research to Risk Assessment, Chem Res Toxicol. 17;27(3):314-329 (2014).
Tox-21c has identified the promise of new technologies and the need for large-scale efforts. There are several research initiatives that revolve around the 3Rs (replacement, refinement, and reduction) principle aiming to establish research solutions, which will reduce and eventually replace animal testing in product safety assessment.
Harm reduction and modified risk tobacco products
Smoking is addictive and causes a number of serious diseases such as cardiovascular diseases, lung cancer and chronic obstructive pulmonary disease. It is estimated worldwide that more than one billion people will continue to smoke in the foreseeable future. Providing reduced-risk alternatives to adult smokers who would otherwise continue smoking cigarettes is the basis of “tobacco harm reduction”. Philip Morris International is therefore developing novel products that may have the potential to reduce smoking-related disease risk compared to combustible cigarettes. Our objective with Reduced-Risk Products* (RRPs) is to develop products that reduce or eliminate harmful and potentially harmful constituents, while delivering adult smoker satisfaction.
The evaluation, or quantitative assessment, of the risk reduction potential of RRPs* required the development of sophisticated capabilities in regulatory and systems toxicology, a deep knowledge of the mechanisms that lead to smoking-related diseases and expertise in the design and conduct of clinical studies aimed at substantiating reduced exposure and risk in adult smokers.
To determine whether a Reduced Risk Product* has the potential to reduce disease risk, we compare their biological impact with that of a combustible reference cigarette (3R4F) on a mechanism-by-mechanism basis.
Our approach to Systems Toxicology
Fig 3: Our approach to quantitative mechanism-based systems impact assessment.
With the unprecedented amounts of data accompanying various high throughput technologies, new computational approaches are being developed to facilitate robust analysis and interpretation of these large datasets. Questions arise as to how we can best manage the uncertainties inherent in the application of systems biology information to safety testing. Specifically, how can one ensure the validity of systems biology-based approaches and the resulting information?
With a goal to maintain scrutiny in data analysis and interpretation, we have recently proposed a systems biology verification process and a methodology for verifying the output of research processes in industry.