Standardizing Non-Targeted Analysis Reporting to Advance Exposure Science and Environmental Epidemiology

Targeted chemical analyses have long provided gold-standard monitoring data that support exposure science and environmental epidemiology studies and eventual risk-based decisions. Despite this demonstrated utility, the advent of exposomics in 2005 yielded widespread recognition that “all” exposures encapsulate vastly more than the hundreds of routinely monitored, targeted chemical analytes [1]. To address this gap, non-targeted analysis (NTA) methods that utilize high-resolution mass spectrometry (HRMS) have emerged as the primary analytical tools for examining chemical stressors and stress response markers without a priori knowledge of sample content. These methods enable more comprehensive characterization of the exposome at both individual (e.g., analyzing a blood sample from a person) and community (e.g., tracking chemical fingerprints in wastewater) levels. As examples of successful implementation of NTA methods, recent applications have characterized the widespread presence of previously unidentified per- and polyfluoroalkyl substances (PFAS) in New Jersey soils [2], linked air pollution exposure to unique metabolic markers and pathways underlying the pathogenesis of cardiopulmonary disease [3], and identified potentially toxic environmental contaminants in the sera of pregnant women [4] and in human breastmilk [5].

In light of these (and many other) examples, NTA approaches clearly offer tremendous capabilities for more comprehensive exposure characterization. For the first time in history, researchers can consider a greatly expanded scope of chemical analytes when determining which stressors (individual or combined) are most strongly associated with impaired biological function and disease. Despite this potential, NTA methods remain complex and diverse, presenting considerable barriers to the immediate utilization of NTA data by exposure scientists, epidemiologists, and decision makers. Standardized approaches are therefore needed to aid in the generation, reporting, and review of NTA data [6–11]. The NTA Study Reporting Tool (SRT), recently developed by the Benchmarking and Publications for Non-Targeted Analysis (BP4NTA) working group, is a timely response to this need [12–14].

The SRT was explicitly conceived and developed to improve the quality of NTA study reporting. It is a downloadable and fillable template designed to assist authors and reviewers of NTA research manuscripts and proposals. As shown in the graphical abstract, individual cells of the SRT template represent research sections (i.e., Methods and Results), categories (e.g., Study Design and Data Acquisition), and sub-categories (e.g., Objectives & Scope and Analytical Sequence) that are applicable to most NTA studies. These cells are organized in a sequential manner that follow the typical progression of any NTA project. The SRT facilitates the evaluation of research reporting quality (not scientific merit) in each defined sub-category using a color-coded, 4-level scoring system (0 to 3, or “NA” if certain criteria are not relevant), with space reserved for written reviewer rationales.

The BP4NTA website [15] hosts the version-controlled SRT, which is available for download in both Excel [13] and PDF [14] formats. Both file formats support anonymity, allowing blinded peer review in accordance with journal policies (where applicable). A score plotting feature (Excel only, designed for editors) and a detailed score explanation table facilitate interpretation of SRT results. Notably, each SRT sub-category is accompanied by detailed reference content available on the BP4NTA website that provides background information for users less familiar with certain aspects of NTA workflows. Step-by-step instructional videos are also available on the BP4NTA website to guide first-time SRT users [16–17]. Together, the SRT and supporting educational materials are invaluable resources for NTA beginners, practitioners, reviewers, and stakeholders looking to better design, implement, review, and understand NTA studies.

While the SRT is intended to improve (and even standardize) NTA reporting, it is not prescriptive in terms of how NTA studies should be conducted. Rather, it provides guidance to researchers to ensure that critical elements of a study are reported so that methods and results can be rigorously evaluated and reproduced. Although focused on reporting quality (not data quality), the SRT may also highlight potential strengths and weaknesses of evaluated studies, further enabling meaningful interpretation of results. Accordingly, we anticipate that the SRT will benefit users not only during study design and manuscript/proposal preparation, but also at multiple points throughout the peer review process (Figure 1).

Figure 1.

The NTA Study Reporting Tool (SRT) can be used in a variety of applications throughout the scientific lifecycle. From researcher education and study planning to manuscript/proposal preparation, review, and acceptance, the SRT provides a framework to improve NTA reporting and transparency.

In addition to providing a framework for thorough and efficient manuscript/proposal preparation and review [18–19], the SRT offers editors and decision-makers a clear means to adjudicate assembled reviews. For those who generally submit NTA research to the Journal of Exposure Science Environmental Epidemiology (JESEE), recommendations for SRT use are currently incorporated into JESEE’s instructions to authors, referees, and editors. Although use is not required, the SRT may be used during the initial submission or at the request of the editor as part of the revision submission. To emphasize use of the SRT at JESEE and provide an example for SRT adoption by other journals, submitting authors and peer reviewers contributing to the “Exposomics Using Non-Targeted Analysis” special topic issue of JESEE are receiving additional guidance about and encouragement to implement the SRT from the editorial team. Follow-up surveys will also evaluate author and reviewer use of the SRT during the special topic issue to inform continued implementation at JESEE.

To ensure transparent use of the SRT during publication, and enable long-term evaluation of SRT adoption/impact, instructions for citation/acknowledgement are provided for authors and reviewers (Table 1). When consulted during manuscript preparation or study design, the SRT should be cited as a standard reference, per journal guidelines (including the original publication describing its development [12] and the PDF [13] or Excel [14] tool itself). Likewise, when the SRT is used by reviewers as part of the publication process, authors are encouraged to acknowledge the SRT (noting the Peter et al. DOI and the PDF or Excel tool DOI) in an author-controlled text field (e.g., the “Acknowledgements” section).

Table 1.

Citing or Acknowledging Use of the SRT in Manuscript Preparation or Review

SRT Use	Reference Location	Mechanism	Template Language
Manuscript Preparation	Cited in the “Methods” section	Authors cite SRT use directly	The NTA Study Reporting Tool (SRT) was used in the preparation of this manuscript (Peter et al., 2021; 10.6084/m9.figshare.19763482 [PDF] or 10.6084/m9.figshare.19763503 [Excel]).
Manuscript Review	Noted in the “Acknowledgements” section	Reviewers and editors encourage authors to acknowledge SRT use	The NTA Study Reporting Tool (SRT) was used in the review of this manuscript and is attached to my reviewer comments. More information on the SRT can be found at www.nontargetedanalysis.org/SRT. To enable future assessment of its impact on NTA reporting, please acknowledge its use in the Acknowledgements section of your manuscript: “The NTA Study Reporting Tool (SRT) was used during peer review to document and improve the reporting and transparency of this study (10.1021/acs.analchem.1c02621; 10.6084/m9.figshare.19763482 [PDF] or 10.6084/m9.figshare.19763503 [Excel]).”

We anticipate that widespread utilization of the SRT during study design, manuscript/proposal preparation, and peer review will yield noticeable improvements in the reporting quality of NTA studies and lend added credibility to NTA research findings. NTA remains a relatively new analytical approach, with ongoing efforts to harmonize myriad aspects of complex workflows (ranging from data acquisition to quality control and performance assessment) [20]. Establishing universal expectations for NTA study reporting facilitates clear and transparent communication about NTA methods and results, laying a foundation for subsequent efforts to evaluate and compare NTA data quality. Ultimately, we envision that JESEE’s incorporation of the SRT into the peer review process will accelerate a tangible increase in NTA data utilization in exposure science and environmental epidemiology studies.

Although BP4NTA members are already individually adopting the SRT during their own manuscript/proposal preparation and peer review (and encouraging colleagues to do the same), we recommend formally incorporating the SRT into the entire scientific process as shown in Figure 1. Documented and widespread use will create opportunities to evaluate how the SRT is applied, examine its impact on reporting in the field, and obtain additional community feedback (via a comment box available on the BP4NTA website) that will inform future updates to the tool. High quality reporting is crucial to making NTA research and data accessible, reproducible, trusted, and useful to stakeholders, regulators, and other decision makers. JESEE editors recognize the need to set a new standard for NTA reporting, with the journal being at the forefront of SRT adoption. Ultimately, the guidance provided by the SRT will enable objective review of complex and diverse NTA-based exposomics studies, supporting confident utilization of next-generation exposure data.