Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies

Abstract

The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data. This guide provides a higher-level hierarchy of tumor types or categories correlating the tumor names from the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer’s guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature; as SEND and INHAND terminology and information evolve, this guide will be updated.

Keywords

tumor combination tumor statistical analysis SEND INHAND neoplasm carcinogenicity studies

Introduction

This guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology (Society of Toxicologic Pathology [STP], British Society of Toxicologic Pathology [BSTP], European Society of Toxicologic Pathology [ESTP]), the FDA, the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) initiative, and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, with a primary goal of assisting pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer-review pathologists in interpreting the tumor data. This guide provides a human-readable, user friendly, higher-level hierarchy of tumor types or categories correlating the tumor names from the INHAND publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer’s guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature, as SEND and INHAND terminology and information evolve, this guide, effective September 13, 2023, will be updated. The guide is available on the Clinical Data Interchange Standards Consortium (CDISC) CT website at https://www.cdisc.org/standards/terminology/controlled-terminology and scroll down to Supplemental Files.

Background

The SEND is an implementation of the CDISC Standard Data Tabulation Model (SDTM) which specifies a way to share nonclinical data in a consistent format. Data from general toxicology and carcinogenicity studies started after December 17, 2016, must be submitted in the data formats supported by FDA and listed in the FDA Data Standards Catalog. This applies to new drug applications (NDAs), biological license applications (BLAs), abbreviated new drug applications (ANDAs), and subsequent submissions to these types of applications. For investigational new drugs (INDs), the requirement applies for studies that start after December 17, 2017.

A SEND package consists of several components, but the main focus is on individual study endpoint data. Endpoints typically map to domains (essentially, datasets), with a number of variables (a.k.a., columns or fields). The SEND is in production and available for use (https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources). Tumor data in nonclinical studies are currently included in the microscopic (MI) domain of SEND. The CT (CDISC SEND) for a tumor finding for an animal is mapped to microscopic standardized result (MISTRESC) in SEND which includes information related to tumor type and malignancy status.

With the primary goal of assisting users of SEND data, the FDA requested guidance from the SEND CT Core Team to review and recommend which tumors from the NEOPLASM CT code list in SEND could routinely be combined for statistical analyses of tumor findings from carcinogenicity studies. Previously, biostatisticians and pharmacology/toxicology FDA reviewers used two key references. In 1986, general guidelines were published by McConnell et al¹¹ for combining tumors in rodent carcinogenicity studies. This was followed in 2010 by an update and extension of the McConnell publication by Brix et al.⁴ The SEND CT implemented a working group with expert pathologists and biopharmaceutical scientists to review literature, commencing with the 2010 publication and published INHAND documents^{1-3,5-10,12-16,18,19} to provide recommendations for tumor combinations with more details than provided in these publications. The working group was composed of an INHAND/SEND liaison who served as the group leader, veterinary pathology experts from international societies of toxicologic pathology, FDA biostatistician and nonclinical review representatives, a SEND CT liaison, representatives from the STP Scientific and Regulatory Policy Committee (SRPC), INHAND experts, a National Institutes of Health (NIH) Terminology Services/SDTM CT liaison, and a SEND Business Integrator. This guide relates each tumor name in the NEOPLASM code list to a higher-level tumor group to support combinations for statistical analysis of tumor data. All combination recommendations in this document should serve as a guide when determining which combinations may be warranted for statistical analysis and should not be interpreted as a recommendation to carry out the combination statistical analysis on every occasion. The STP provided support for this effort and the INHAND organ working groups had the opportunity to review and comment on recommended combinations of tumor types.

How to Use This Guide

The information is organized in a tabular format with a column heading, followed by a brief note on what is contained within the column (Table 1). The SEND Tumor Codes are listed for individual tumors and not for the possible combinations. Cells highlighted in dark gray in columns F and G show relevant tumor combinations. Some tumor terms are not listed in INHAND but are available in SEND and vice versa—this will be noted in the cell. Tumors that can occur throughout the body including, but not limited to, lymphoma, vascular tumors, and soft-tissue tumors (such as fibroma or lipoma), will not be listed in every possible organ. Tumors in SEND CT that pertain to nonrodent species, are nonspecific, or older terms no longer in use, will not be listed here as these terms are not in scope. The naming conventions for tumors in SEND include “benign” and “malignant” within the submission value, while the naming conventions in INHAND only include “benign” or “malignant” if the tumor name is unclear without it. Site is defined as region, location, or zones within a defined tissue. The NCI C-codes associated with the SEND organ and tumor names are relevant to the 2023-06-30 version of SEND CT. Examples of this organization method for select nervous system tumors are provided in Figure 1A and B.

Table 1.

Template of tabulated information.

No. of row	Organ system	INHAND organ name	SEND organ name	SEND specimen (organ) code	INHAND tumor name and tumor combinations	SEND tumor name and tumor combinations	SEND tumor code	Related tumor names(s) in SEND	Tumor group name (cell type/biological behavior)	Tumor groups combined for analysis	Tumor groups not combined for analysis	Comments	References
Used for sorting the groups	The name of the organ systems, based on INHAND publications. These are general groupings and not intended to align with BODSYS (Body Systems) in SEND.	This column is for the tissue name in INHAND	This column is for the specimen name in SEND. Major organs are listed; tumor combinations can apply to suborgans in SEND that relate to a major organ.	This column is for the SEND specimen code	This column is for the INHAND tumor terms and the combination of tumors. The combinations listed are all potential tumor types and studies may have subsets of tumors listed.	This column is for the tumor terms from SEND and the combination of tumors. The combinations listed are all potential tumor types and studies may have subsets of tumors listed.	This column is for the SEND tumor code	This column is for SEND tumor terms related to the main terms listed. Examples include subtypes of tumor diagnoses or legacy diagnoses and these would be analyzed similar to the main terms.	This column provides a designation for the tumor combinations based on general cell type and biologic behavior.	This column provides the recommended tumor combinations for each organ.^a These tumors are specific to the organ in which they are listed.	Only combinations in the previous column should be followed. This column contains specific exclusions to the recommended combinations.^b	This column is used for comments about the cell type, if relevant, and other information that might be helpful.	This column is for specific citations.

Abbreviations: INHAND = International Harmonization of Nomenclature and Diagnostic Criteria; SEND = Standard for Exchange of Nonclinical Data.

Standard wording such as “1. Analyze these tumors within the site. 2. Combine these tumors for analysis in the A, B, C suborgans.” can be used if this fits with the organ system. Some organ systems may require more specific wording for the recommended analyses.

Standard wording: “Do not combine these tumors and/or sites for analysis.”

The approach to determining appropriate combinations of tumors for analysis is outlined below. For all analyses, sexes are analyzed separately.

A. Standard Analysis

1. Analyze each tumor type separately by site.

2. Combinations

a. Combine benign tumors of the same cell type by site for analysis.

b. Combine malignant tumors of the same cell type by site for analysis.

c. Combine benign and malignant tumors of the same cell type by site for analysis.

3. Systemic tumors such as lymphomas/leukemias that, in the data set, are combined into a single organ or tissue such as “Whole Body,” “Hematopoietic Tumors,” and so on, follow the standard analysis. For these types of tumors, the incidence of tumors of the same cell type should be determined on a whole animal basis (ie, number of animals in which the tumor was observed at any site, rather than the total number of tumors).

B. Systemic Tumors such as vascular tumors, selected mesenchymal tumors, and so on, that are diagnosed in individual organs in the data set may also be combined as indicated in the spreadsheets. Analysis of such tumors is generally done according to the following guidelines.

1. Follow the guidelines for the standard analysis.

2. Analyze tumors of the same cell type across all appropriate sites. For these types of tumors, the incidence of tumors of the same cell type should be determined on a per animal basis (ie, number of animals in which the tumor was observed at any site, rather than the total number of tumors).

a. Combine benign tumors of the same cell type by tumor bearing animals.

b. Combine malignant tumors of the same cell type by tumor bearing animals.

c. Combine benign and malignant tumors of the same cell type by tumor bearing animals.

3. Both site-specific and whole-body analyses may be needed in order to determine whether there is a positive effect.

C. Rarely, it may be appropriate to combine tumors of different tissues within an organ system, and rationale should be provided in the study report.

Examples of Scenarios A, B, and C are given below.

Example Scenario A: Lung Tumors—Rat Carcinogenicity Study

An example of a tumor incidence table for lung is shown below with a stepwise approach to combine tumor types. The first step is to analyze individual lung tumors as listed in Table 2.

Table 2.

Example Scenario A. Steps of lung tumor-combinations and analyses.

Dose group	Control	Low	Mid	High
Number of rats/group	50 males	50 males	50 males	50 males
First step
Tumors^a
Adenoma, bronchioloalveolar, benign	1	4	2	1
Carcinoma, bronchioloalveolar, malignant	0	1	0	2
Epithelioma, nonkeratinizing, benign	0	0	0	1
Carcinoma, squamous cell, malignant	1	2	0	4
Papilloma, squamous cell, benign	0	1	0	0
Neuroendocrine tumor, benign	1	0	0	0
Neuroendocrine tumor, malignant	0	1	0	4
Second step
Tumors^b
Adenoma, bronchioloalveolar, benign	1	4	2	1
Papilloma, squamous cell, benign	0	1	0	0
Epithelioma, nonkeratinizing, benign	0	0	0	1
Total benign epithelial tumors	1	5	2	2
Third step
Tumors^c
Carcinoma, bronchioloalveolar, malignant	0	1	0	2
Carcinoma, squamous cell, malignant	1	2	0	4
Total malignant epithelial tumors	1	3	0	6
Fourth step
Analysis of Epithelial Tumors^d
Adenoma, bronchioloalveolar, benign/Papilloma, squamous cell, benign/Epithelioma, nonkeratinizing, benign	1	5	2	2
Carcinoma, bronchioloalveolar, malignant/Carcinoma, squamous cell, malignant	1	3	0	6
Total benign and malignant epithelial tumors	2	8	2	8
Analysis of neuroendocrine tumors
Tumors^e
Neuroendocrine tumor, benign	1	0	0	0
Neuroendocrine tumor, malignant	0	1	0	4
Total benign and malignant neuroendocrine tumors	1	1	0	4

Analyze each tumor in this step separately.

Analyze combined benign epithelial tumors.

Analyze combined malignant epithelial tumors.

Analyze combined benign and malignant epithelial tumors.

Analyze combined benign and malignant neuroendocrine tumors.

The bold will distinguish those tumors that should be combined.

The second step is to combine the benign tumors that have the same cell type of origin. Adenoma, papilloma, and epithelioma are all epithelial cell tumors (Table 2). Neuroendocrine tumor is a different cell of origin and would be analyzed separately. The third step is to combine the malignant lung tumors (Table 2) that have the same cell type of origin. The fourth step is to combine the benign and malignant lung tumors shown in the previous tables for analysis (Table 2) that have the same cell type of origin. In this hypothetical data set, squamous cell tumors are combined with other epithelial tumors in the lung for analysis as an example of combinations that can be performed based on the professional judgment of the pathologist in consideration of the data. Although the cell of origin for squamous tumors in the lung has not been definitively identified, it is likely from bronchial, bronchiolar, or alveolar epithelium.¹⁷

As previously noted, the neuroendocrine tumors (Table 2) should be analyzed separately.

Some tumor/organ site combinations may be more complex than this example as detailed and explained in spreadsheets for each organ system/individual organ.

Example Scenario B: Vascular Tumors—Rat Carcinogenicity Study

Vascular tumors may be recorded by the specific organ where they occur and/or under a “designated organ name” such as “Whole Body” or “Systemic Tumors” added to the histopathology data capture program for the study. In the first case, when these tumors are recorded by organ, all 4 steps as described in Scenario A should be followed sequentially. When the tumors are recorded under whole body, only step 4 is applicable (see below).

An example of an incidence table for a tumor type (benign and/or malignant) that may occur in multiple organs is shown in Table 3 with the stepwise approach taken to combine and evaluate vascular tumors for analysis. The first step is to analyze hemangioma separately by site and hemangiosarcoma separately by site as shown in Table 3. In the second step, benign hemangioma and malignant hemangiosarcoma are combined by site per animal for analysis as shown in Table 3. In the third step, the totals of hemangioma, benign (by animal) and hemangiosarcoma, malignant (by animal) are analyzed (Table 3). This may be captured under “Whole body” in the Organ Tables in some laboratories while others will not have such a designation a priori. In the fourth step hemangioma, benign and/or hemangiosarcoma, malignant within each animal are combined across whole body in Table 3.

Table 3.

Example scenario B: steps of vascular tumor combinations and analyses.

Dose group	Control	Low	Mid	High
Number of rats/group	50 males	50 males	50 males	50 males
First step
Organ—tumor^a
Liver—hemangioma, benign	0	1	1	1
Liver—hemangiosarcoma, malignant	2	1	1	2
Mesenteric lymph node—hemangioma, benign	1	0	0	1
Mesenteric lymph node—hemangiosarcoma, malignant	3	4	3	7
Skin/subcutis—hemangioma, benign	1	1	2	2
Skin/subcutis—hemangiosarcoma, malignant	1	0	1	2
Spleen—hemangioma, benign	0	1	0	0
Spleen—hemangiosarcoma, malignant	1	0	1	2
Second step
Organ—tumor^b
Liver—hemangioma, benign	0	1	1	1
Liver—hemangiosarcoma, malignant	2	1	1	2
Liver—hemangioma, benign/hemangiosarcoma, malignant	2	2	2	3
Mesenteric lymph node—hemangioma, benign	1	0	0	1
Mesenteric lymph node—hemangiosarcoma, malignant	3	4	3	7
Mesenteric LN—hemangioma, benign/hemangiosarcoma, malignant	4	4	3	8
Skin/subcutis—hemangioma, benign	1	1	2	2
Skin/subcutis—hemangiosarcoma, malignant	1	0	1	2
Skin/subcutis—hemangioma, benign/hemangiosarcoma, malignant	2	1	2 ^c	3 ^c
Spleen—hemangioma, benign	0	1	0	0
Spleen—hemangiosarcoma, malignant	1	0	1	2
Spleen—hemangioma, benign/hemangiosarcoma, malignant	1	1	1	2
Third step
Tumors^d
Whole body (animal)—hemangioma, benign	2	2^e	3	4
Whole body (animal)—hemangiosarcoma, malignant	4^e	5	5^e	9^e
Fourth step^f
Whole body (animal)—hemangioma, benign	2	2	3	4
Whole body (animal)—hemangiosarcoma, malignant	4	5	5^g	9^g
Whole body (animal)—hemangioma, benign/hemangiosarcoma, malignant	6	7	7 ^g	12 ^g

Analyze each tumor in this step separately.

Analyze combined benign and malignant vascular tumors within individual organs.

Organ totals for a tumor may not add up precisely when combining individual sites, as some animals in a group may have more than one primary tumor diagnosed within an organ (eg, skin/subcutis with both a benign tumor and malignant tumor at separate locations within the tissue but in the same animal, in the mid- and high-dose groups).

Analyze benign and malignant vascular tumors separately on an animal basis.

Whole body (animal) totals may not add up precisely when combining individual sites, as some animals may have a primary tumor diagnosed for more than one location.

Analyze combined benign and malignant vascular tumors on an animal basis.

Whole body (animal) individual and combined tumor totals may not add up precisely as some animals may have a benign and/or a malignant primary tumor designated in more than one location. The vascular tumor combination is counted once per animal even if there may be multiple tumors of the same cell type (ie, vascular tumors) in different organs of an animal.

The bold will distinguish those tumors that should be combined.

Example Scenario C: Uterine/Cervical Tumors—Rat Carcinogenicity Study

An example of an incidence table for a tumor type (benign and/or malignant) that may occur in multiple organs is shown in the table below with the stepwise approach taken to combine and evaluate these epithelial tumors that occur in the cervix and uterus for analysis. Table 4 is an example of epithelial tumors (benign and/or malignant) that may occur in different organs of the same organ system, such as uterus and cervix. In the first step, each of the epithelial tumor types in Table 4 is analyzed separately by site. In the second step, benign tumors and malignant tumors that have the same cell type are combined by site for analysis (Table 4).

Table 4.

Example scenario C: steps of uterine/cervical tumor-combinations and analyses.

Dose group	Control	Low	Mid	High
Number of rats/group	50 females	50 females	50 females	50 females
First step
Organ—tumor^a
Uterus—adenoma, endometrium, benign	0	1	1	1
Uterus—adenocarcinoma, endometrium, malignant	2	1	1	5
Uterus—carcinoma, adenosquamous, malignant	0	0	0	2
Cervix—carcinoma, adenosquamous, malignant	0	0	0	2
Cervix—carcinoma, squamous cell, malignant	0	1	0	0
Cervix—papilloma, squamous cell, benign	0	1	0	1
Second step
Organ/tumor^b
Uterus—adenoma, endometrium, benign	0	1	1	1
Uterus—adenocarcinoma, endometrium, malignant	2	1	1	5
Uterus—adenoma, endometrium, benign/adenocarcinoma, endometrium, malignant	2	2	2	6
Cervix—carcinoma, squamous cell, malignant	0	1	0	0
Cervix—papilloma, squamous cell, benign	0	1	0	1
Cervix—papilloma squamous cell, benign/carcinoma, squamous cell, malignant	0	2	0	1
Third step
Organ/tumor^c
Uterus—adenocarcinoma, endometrium, malignant	2	1	1	5
Uterus—carcinoma, adenosquamous, malignant	0	0	0	2
Uterus—adenocarcinoma, endometrium, malignant/carcinoma, adenosquamous, malignant (all malignant epithelial tumors of uterus)	2	1	1	7
Cervix—carcinoma, squamous cell, malignant	0	1	0	0
Cervix—carcinoma, adenosquamous, malignant	0	0	0	2
Cervix—carcinoma, squamous cell, malignant/carcinoma, adenosquamous, malignant (all malignant epithelial tumors of cervix)	0	1	0	2
Fourth step
Tumors^d
Uterus—carcinoma, adenosquamous, malignant	0	0	0	2
Cervix—carcinoma, adenosquamous, malignant	0	0	0	2
Uterus/cervix—carcinoma, adenosquamous, malignant	0	0	0	4
Fifth step
Tumors^e
Uterus—adenoma, endometrium, benign	0	1	1	1
Cervix—papilloma, squamous cell, benign	0	1	0	1
Uterus/cervix—adenoma, endometrium, benign/papilloma, squamous cell, benign	0	2	1	2
Uterus—adenocarcinoma, endometrium, malignant	2	1	1	5
Uterus—carcinoma, adenosquamous, malignant	0	0	0	2
Cervix—carcinoma, squamous cell, malignant	0	1	0	0
Cervix—carcinoma, adenosquamous, malignant	0	0	0	2
Uterus/cervix—adenocarcinoma, endometrium, malignant/carcinoma, adenosquamous, malignant/carcinoma, squamous cell, malignant	2	2	1	9
Uterus/cervix—adenocarcinoma, endometrium, malignant/carcinoma, adenosquamous, malignant/carcinoma, squamous cell, malignant/adenoma, endometrium, benign/papilloma, squamous cell, benign	2	4	2	11

Analyze each tumor in this step separately.

Analyze combined benign and malignant tumors within individual organs.

Analyze all benign and malignant epithelial tumors of same cell of origin separately within the uterus and cervix.

Analyze combined malignant tumors of uterus and cervix.

Analyze combined benign and malignant tumors of uterus and cervix together as uterus/cervix.

The bold will distinguish those tumors that should be combined.

In the third step, all benign epithelial tumors of same cell of origin and all malignant epithelial tumors of same cell of origin are combined by site for analysis (Table 4). Note in this example, only one type of benign epithelial tumor occurred in the uterus and cervix to combine across sites; therefore, no benign tumor combinations appear in this table. In the fourth step, all benign tumors of the same cell type and all malignant tumors of the same cell type are combined between sites of uterus and cervix for analysis (Table 4). Note in this example, only one type of benign epithelial tumor occurred in the uterus or cervix to combine across sites; therefore, no benign tumor combinations appear in the table.

In the fifth step, all benign tumors of the same cell of origin and all malignant tumors of the same cell of origin are combined between sites of uterus and cervix (Table 4). It should be noted that if the protocol tissue is uterus/cervix, step 1 is benign tumors of this site, step 2 is malignant tumors of this site, and step 3 is combined benign/malignant of this site.

Conclusion

This tumor combination guide offers a human-readable, user friendly, higher-level hierarchy of tumor types or categories correlating the tumor names from INHAND publications with those available in the NEOPLASM CT code list in SEND and will be useful to regulatory reviewers, study and peer-review pathologists in evaluating tumor data. It should be noted that this document is a guide, and situations may arise that require a different approach. If there is a compelling, study-specific rationale to combine tumors in situations where the recommendation is to “not combine,” the study pathologist should provide that rationale in the study report.

Supplemental Material

sj-tif-1-tpx-10.1177_01926233241230553 – Supplemental material for Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies

Supplemental material, sj-tif-1-tpx-10.1177_01926233241230553 for Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies by Charlotte Keenan, Muthafar Al-Haddawi, Jean-Guy Bienvenu, Alys Elizabeth Bradley, Paul Brown, Hepei Chen, Karyn Colman, Michael Elwell, Nicholas Gatto, Dawn Goodman, Binod Jacob, Lynda Lanning, LuAnn McKinney, Erin Muhlbradt, Rick Perry, Alessandro Piaia, Daniel Potenta, Karen S. Regan, Benjamin Sefing, Michael Thibodeau, Erin Tibbs-Slone, Jochen Woicke and Craig M. Zwickl in Toxicologic Pathology

Supplemental Material

sj-tif-2-tpx-10.1177_01926233241230553 – Supplemental material for Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies

Supplemental material, sj-tif-2-tpx-10.1177_01926233241230553 for Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies by Charlotte Keenan, Muthafar Al-Haddawi, Jean-Guy Bienvenu, Alys Elizabeth Bradley, Paul Brown, Hepei Chen, Karyn Colman, Michael Elwell, Nicholas Gatto, Dawn Goodman, Binod Jacob, Lynda Lanning, LuAnn McKinney, Erin Muhlbradt, Rick Perry, Alessandro Piaia, Daniel Potenta, Karen S. Regan, Benjamin Sefing, Michael Thibodeau, Erin Tibbs-Slone, Jochen Woicke and Craig M. Zwickl in Toxicologic Pathology

Footnotes

Acknowledgements

The authors wish to express their thanks to the STP Scientific and Regulatory Policy Committee and the INHAND Organ Working Groups for their scientific review and editorial input to this manuscript.

Disclaimer

This article reflects the views of the authors and should not be construed to represent the FDA’s views or policies.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Charlotte Keenan

Alys Elizabeth Bradley

Paul Brown

Karyn Colman

Nicholas Gatto

Erin Tibbs-Slone

Jochen Woicke

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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