Novel text analytics approach to identify relevant literature for human health risk assessments: A pilot study with health effects of in utero exposures.

BACKGROUND: Systematic reviews involve mining literature databases to identify relevant studies. Identifying potentially relevant studies can be informed by computational tools comparing text similarity between candidate studies and selected key (i.e., seed) references. Challenge Using computational approaches to identify relevant studies for risk assessments is challenging, as these assessments examine multiple chemical effects across lifestages (e.g., human health risk assessments) or specific effects of multiple chemicals (e.g., cumulative risk). The broad scope of potentially relevant literature can make selection of seed references difficult. Approach We developed a generalized computational scoping strategy to identify human health relevant studies for multiple chemicals and multiple effects. We used semi-supervised machine learning to prioritize studies to review manually with training data derived from references cited in the hazard identification sections of several US EPA Integrated Risk Information System (IRIS) assessments. These generic training data or seed studies were clustered with the unclassified corpus to group studies based on text similarity. Clusters containing a high proportion of seed studies were prioritized for manual review. Chemical names were removed from seed studies prior to clustering resulting in a generic, chemical-independent method for identifying potentially human health relevant studies. We developed a case study that focused on identifying the array of chemicals that have been studied with respect to in utero exposure to test the recall of this novel literature searching strategy. We then evaluated the general strategy of using generic, chemical-independent training data with two previous IRIS assessments by comparing studies predicted relevant to those used in the assessments (i.e., total relevant). Outcome A keyword search designed to retrieve studies that examined the in utero effects of environmental chemicals identified over 54,000 candidate references. Clustering algorithms were applied using 1456 studies from multiple IRIS assessments with chemical names removed as training data or seeds (i.e., semi-supervised learning). Using a six-algorithm ensemble approach 2602 articles, or approximately 5% of candidate references, were "voted" relevant by four or more clustering algorithms and manual review confirmed nearly 50% of these studies were relevant. Further evaluations on two IRIS assessments, using a nine-algorithm ensemble approach and a set of generic, chemical-independent, externally-derived seed studies correctly identified 77-83% of hazard identification studies published in the assessments and eliminated the need to manually screen more than 75% of search results on average. Limitations The chemical-independent approach used to build the training literature set provides a broad and unbiased picture across a variety of endpoints and environmental exposures but does not systematically identify all available data. Variance between actual and predicted relevant studies will be greater because of the external and non-random origin of seed study selection. This approach depends on access to readily available generic training data that can be used to locate relevant references in an unclassified corpus. Impact A generic approach to identifying human health relevant studies could be an important first step in literature evaluation for risk assessments. This initial scoping approach could facilitate faster literature evaluation by focusing reviewer efforts, as well as potentially minimize reviewer bias in selection of key studies. Using externally-derived training data has applicability particularly for databases with very low search precision where identifying training data may be cost-prohibitive.

Mutation of the little finger domain in human DNA polymerase η alters fidelity when copying undamaged DNA.

DNA polymerase η (pol η) synthesizes past cyclobutane pyrimidine dimer and possibly 7,8-dihydro-8-oxoguanine (8-oxoG) lesions during DNA replication. Loss of pol η is associated with an increase in mutation rate, demonstrating its indispensable role in mutation suppression. It has been recently reported that ß-strand 12 (amino acids 316-324) of the little finger region correctly positions the template strand with the catalytic core of the enzyme. The authors hypothesized that modification of ß-strand 12 residues would disrupt correct enzyme-DNA alignment and alter pol η's activity and fidelity. To investigate this, the authors purified proteins containing the catalytic core of the polymerase, incorporated single amino acid changes to select ß-strand 12 residues, and evaluated DNA synthesis activity for each pol η. Lesion bypass efficiencies and replication fidelities when copying DNA-containing cis-syn cyclobutane thymine-thymine dimer and 8-oxoG lesions were determined and compared with the corresponding values for the wild-type polymerase. The results confirm the importance of the ß-strand in polymerase function and show that fidelity is most often altered when undamaged DNA is copied. Additionally, it is shown that DNA-protein contacts distal to the active site can significantly affect the fidelity of synthesis.

Biochemical analysis of active site mutations of human polymerase η.

DNA polymerase η (pol η) plays a critical role in suppressing mutations caused by the bypass of cis-syn cyclobutane pyrimidine dimers (CPD) that escape repair. There is evidence this is also the case for the oxidative lesion 7,8-dihydro-8-oxo-guanine (8-oxoG). Both of these lesions cause moderate to severe blockage of synthesis when encountered by replicative polymerases, while pol η displays little no to pausing during translesion synthesis. However, since lesion bypass does not remove damaged DNA from the genome and can possibly be accompanied by errors in synthesis during bypass, the process is often called 'damage tolerance' to delineate it from classical DNA repair pathways. The fidelity of lesion bypass is therefore of importance when determining how pol η suppresses mutations after DNA damage. As pol η has been implicated in numerous in vivo pathways other than lesion bypass, we wanted to better understand the molecular mechanisms involved in the relatively low-fidelity synthesis displayed by pol η. To that end, we have created a set of mutant pol η proteins each containing a single amino acid substitution in the active site and closely surrounding regions. We determined overall DNA synthesis ability as well as the efficiency and fidelity of bypass of thymine-thymine CPD (T-T CPD) and 8-oxoG containing DNA templates. Our results show that several amino acids are critical for normal polymerase function, with changes in overall activity and fidelity being observed. Of the mutants that retain polymerase activity, we demonstrate that amino acids Q38, Y52, and R61 play key roles in determining polymerase fidelity, with substation of alanine causing both increases and decreases in fidelity. Remarkably, the Q38A mutant displays increased fidelity during synthesis opposite 8-oxoG but decreased fidelity during synthesis opposite a T-T CPD.