Example of a human expert segmentation (A) compared with automated segmentation from commercially-available region growing–based segmentation technique before (B) and after (C) human adjustment of settings, and automated segmentations from the top artificial intelligence algorithm from phase 3 of the contest (D).
A comparison of average performance (point) and standard error (whiskers) based on metrics (A) Dice coefficient, (B) Jaccard Index, and (C) contest-specific segmentation score (S score) of top 7 algorithms from phase 1, top 5 algorithms from phase 2, top 5 algorithms from phase 3, phase 2 ensemble model, and phase 3 ensemble model on the validation (x axis) and holdout data sets (y axis). Performance benchmarks for comparison include commercially available region-growing-based algorithms before (commercial software) and after (commercial software and expert) human intervention, the average of human interobserver comparisons between 6 radiation oncologists, and intraobserver variation in the human expert performing the segmentation task twice independently on the same tumor. Benchmarks are shown as dashed lines (gray bands indicate estimated uncertainties as described in eTable 3 in the Supplement).
A, Histogram of contest-specific segmentation score (S score) on a per-scan basis on the holdout data set compared with the intraobserver benchmark and (B) fraction of scans with performance greater than a given S score as a function the S score (holdout test set) for the phase 3 ensemble solution compared with the intraobserver benchmark. A comparison with the interobserver benchmark is also shown (gray band indicates first and third quartiles). Seventy-five percent of segmentations produced by the ensemble matched the lower threshold of intraobserver variation (S score, 0.60).
eTable 1. Contest Prize Distributions, with payouts based on ranked performance
eTable 2. Common evaluation metrics for comparing segmentations
eTable 3. Algorithm, ensemble, and benchmark performance averaged over all scans in the validation, holdout and external data set
eTable 4. Primary methods, and utilization of supplemental data for training and/or inference
eTable 5. Algorithm, ensemble, and benchmark performance averaged over all scans in the validation and holdout data sets
eTable 6. Algorithm, ensemble, and benchmark performance averaged over all scans in the external data set
eFigure 1. Additional Examples of Human Expert versus Automated Segmentations
eFigure 2. Lung Tumor Volume Distribution in This Study Versus A Publicly-Available Dataset
eFigure 3. Distribution of Segmentation Score (S-score) as a function of V/V0
eFigure 4. Evolution of Winning AI Algorithms During the Multi-Phase Contest
eFigure 5. Performance of Ensemble AI Algorithms in Clinical Sub-Groups
eFigure 6. Performance of Top Segmentation Algorithms from The Contest on an External Dataset
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Mak RH, Endres MG, Paik JH, et al. Use of Crowd Innovation to Develop an Artificial Intelligence–Based Solution for Radiation Therapy Targeting. JAMA Oncol. 2019;5(5):654–661. doi:10.1001/jamaoncol.2019.0159
Can crowd innovation be used to rapidly prototype artificial intelligence (AI) solutions that automatically segment lung tumors for radiation therapy targeting, and can AI performance match expert radiation oncologists for this time- and training-intensive task?
A 3-phase, prize-based crowd innovation challenge over 10 weeks, including 34 contestants who submitted 45 algorithms, identified multiple AI solutions that replicated the accuracy of an expert radiation oncologist in targeting lung tumors and performed the task more rapidly.
On-demand, crowdsourcing methods can be used to rapidly prototype AI algorithms to replicate and transfer expert skill and knowledge to underresourced health care settings and improve the quality of radiation therapy globally.
Radiation therapy (RT) is a critical cancer treatment, but the existing radiation oncologist work force does not meet growing global demand. One key physician task in RT planning involves tumor segmentation for targeting, which requires substantial training and is subject to significant interobserver variation.
To determine whether crowd innovation could be used to rapidly produce artificial intelligence (AI) solutions that replicate the accuracy of an expert radiation oncologist in segmenting lung tumors for RT targeting.
Design, Setting, and Participants
We conducted a 10-week, prize-based, online, 3-phase challenge (prizes totaled $55 000). A well-curated data set, including computed tomographic (CT) scans and lung tumor segmentations generated by an expert for clinical care, was used for the contest (CT scans from 461 patients; median 157 images per scan; 77 942 images in total; 8144 images with tumor present). Contestants were provided a training set of 229 CT scans with accompanying expert contours to develop their algorithms and given feedback on their performance throughout the contest, including from the expert clinician.
Main Outcomes and Measures
The AI algorithms generated by contestants were automatically scored on an independent data set that was withheld from contestants, and performance ranked using quantitative metrics that evaluated overlap of each algorithm’s automated segmentations with the expert’s segmentations. Performance was further benchmarked against human expert interobserver and intraobserver variation.
A total of 564 contestants from 62 countries registered for this challenge, and 34 (6%) submitted algorithms. The automated segmentations produced by the top 5 AI algorithms, when combined using an ensemble model, had an accuracy (Dice coefficient = 0.79) that was within the benchmark of mean interobserver variation measured between 6 human experts. For phase 1, the top 7 algorithms had average custom segmentation scores (S scores) on the holdout data set ranging from 0.15 to 0.38, and suboptimal performance using relative measures of error. The average S scores for phase 2 increased to 0.53 to 0.57, with a similar improvement in other performance metrics. In phase 3, performance of the top algorithm increased by an additional 9%. Combining the top 5 algorithms from phase 2 and phase 3 using an ensemble model, yielded an additional 9% to 12% improvement in performance with a final S score reaching 0.68.
Conclusions and Relevance
A combined crowd innovation and AI approach rapidly produced automated algorithms that replicated the skills of a highly trained physician for a critical task in radiation therapy. These AI algorithms could improve cancer care globally by transferring the skills of expert clinicians to under-resourced health care settings.
Lung cancer remains the second most common cancer, and leading cause of cancer mortality, in the United States1 with approximately 150 000 deaths estimated in 2018. Radiation therapy (RT) plays a critical role in the treatment of this disease, and 20% of early stage (I-II) and 50% of advanced stage (III-IV) lung cancer patients receive RT2 with projections of approximately 96 000 patients requiring this treatment modality in 2020.2,3 The precise and accurate volumetric segmentation of tumors, which determines where the radiation dose is delivered into the patient, is a critical part of RT targeting and planning, and has a direct impact on tumor control and radiation-induced toxic effects. Typically, tumor segmentation is performed manually, slice-by-slice on computed tomography (CT) scans by trained radiation oncologists (Figure 1) (eFigure 1 in the Supplement) and can be extremely time consuming. However, there is significant interobserver variation even among experts (eg, 7-fold variation among 5 experts in 1 study),4,5 and the quality of segmentation may directly impact clinical outcomes.6-8 Even in prospective clinical trials with prespecified RT parameters, major RT planning deviations occur in 8% to 71% of patients and are associated with increased mortality and treatment failure.9
Unlike cancer image analysis for diagnostic purposes, which produces a single binary answer (yes or no) to a single question (“Is a mass present?”), therapeutic tumor segmentation involves interpretation of medical imaging on a voxel-by-voxel basis to classify cancer vs normal organ and incorporates an intrinsic risk-benefit assessment of where the radiation dose is to be delivered. For an expert radiation oncologist, this requires both training and intuition, and experience may directly impact lung cancer outcomes.10 However, this critical human resource is not accessible to many underserved patients in both the United States and globally.11,12 Although approximately 58% of lung cancer cases occur in less developed countries,13 these countries have a staggering shortage of radiation oncologists, with an estimated 23 952 radiation oncologists required in 84 low- and middle-income countries by 2020 yet only 11 803 were available in 2012.14
We used a novel combined approach of crowd innovation and artificial intelligence (AI) to address this unmet need in global cancer care. Crowd innovation has been successfully applied to a variety of genomic and computational biology problems by using prize-based competitions to identify extreme value solutions that outperform those developed by conventional academic approaches.15-18 Online contests expand the pool of potential problem solvers substantially beyond traditional academic expert circles to include individuals with a more diverse set of skills, experience, and perspectives. Artificial intelligence has been successfully applied to diagnostic subspecialties of medicine, such as pathology and radiology. Examples include diagnosis of skin cancers from photographs,19 lung cancer on screening CT images,20,21 retinal diseases using optical coherence tomography,22 and breast cancer using mammograms,23 or pathology specimens.24 However, applying AI techniques to therapeutic processes in medicine has not been equally well explored because of a lack of large data sets that are well curated by medical experts, and the need for AI techniques capable of adjusting to alterations in practice patterns or risk tolerance and style of individual treating physicians for specific diseases.
To address the global shortage of expert radiation oncologists, we designed a crowd innovation contest to challenge an international community of programmers to rapidly produce automated AI algorithms that could replicate the manual lung tumor segmentations of an expert radiation oncologist. To reach this goal, we developed a novel contest design, including:
A well-curated lung tumor data set segmented by an expert clinician for contestants to train and test their algorithms.
An objective scoring system for automatic evaluation of submitted algorithms to provide contestant feedback and final rankings.
Motivating and guiding contestants to produce clinically relevant solutions with a cost-effective prize pool, information sharing, and access to feedback from the expert clinician.
To encompass a range of tumor biology and size, we collected a data set of 461 patients with stage IA to IV non–small cell lung cancer (NSCLC) with planning CT scans obtained prior to RT under a protocol approved by the institutional review board at the Dana-Farber/Harvard Cancer Center. A waiver of informed consent was granted due to the retrospective data collection. The data set comprised 77 942 images (median, 157 images/scan) of which 8144 images had tumor present. All tumors were segmented by a single expert (R.H.M.) with 4 years of RT specialty training and 7 years of subspecialty experience in treating lung cancers. The data set was anonymized and randomly divided by patient into training (n = 229), validation (n = 96), and holdout test sets (n = 136). Additional information is available in the eMethods section of the Supplement.
The median tumor volume was 16.40 cm3 (range, 0.28-1103.74 cm3). The volume distribution was reflective of patients with known lung cancer undergoing therapy and differed from publicly available data sets such as the LIDC/IDRI lung nodule atlas25 (eFigure 2 in the Supplement). Additional patient and tumor summary statistics are provided in the Table.
We conducted our contest on Topcoder.com (Wipro, Bengalaru, India), a commercial platform that hosts online algorithm challenges for a community of more than 1 000 000 programmers who compete for prizes while solving computational problems. The contest was designed with 3 interconnected phases with the results of each phase informing the design of subsequent phases. Participants were oriented to the underlying medical problem and the contest design through online written materials and a video (https://youtu.be/An-YDBjFDV8) of the clinician expert demonstrating the manual lung tumor segmentation task.
The first 2 phases each ran for 3 weeks over 70 calendar days and offered $35 000 and $15 000 prize pools (eTable 1 in the Supplement), respectively, with entry open to anyone registered on the Topcoder platform. The third invitation-only phase ran for 4 weeks, with an additional approximately $5000 in prizes.
The contestants’ algorithms were scored by comparing the volumetric segmentation produced by each algorithm on a given patient’s CT scan (including all CT slices) against the expert’s segmentation. The performance of the contestants’ algorithms were assessed using a custom segmentation score (S score) (eTable 2 in the Supplement), that incorporated both the impact of relative and absolute errors. A higher score reflects an automated segmentation for a given patient’s entire tumor that has a high level of both relative and absolute overlap with the expert’s segmentation. Incorporating absolute error was particularly important in this therapeutic RT segmentation task because missing any volume of tumor would lead to an RT miss and increased likelihood of tumor recurrence. We also analyzed performance using traditional measures of relative error, including the Dice coefficient (Dice) and Jaccard index.
Participants were provided with the full training set (CT scans, expert lung tumor and organ segmentations, and other clinical data), and the CT scans without segmentations from a validation set. During each phase, contestants produced segmentations using their algorithms on the validation set and received real-time evaluation of their algorithm’s performance based on the S score on a public leaderboard. With this feedback, contestants could modify their solution or generate new approaches to improve their scores. At the end of each phase, participants submitted their final algorithms for independent evaluation by the study team on the holdout test data set (which was not available to the contestants), and prizes were distributed to contestants who submitted algorithms generating the highest scores.
Between each phase, the study team including the clinical expert reviewed the winning algorithms’ performance and segmentations on individual patient scans to revise the contest design and objectives in each subsequent phase. In the first phase, the contestants were tasked with producing an algorithm that would both locate the tumor and replicate the expert’s segmentations. After review of phase 1 performance identified deficiencies in tumor localization as the major limiting factor, the contest was redesigned in phase 2 to allow contestants to focus their efforts on the therapeutic task of lung tumor targeting, as opposed to the distinct task of tumor diagnosis. Accordingly, we identified tumor location by providing a randomly generated seed point within each tumor, and asked the contestants to optimize their algorithms with that a priori knowledge.
The top 5 contestants from phase 2 were invited to work with the investigators in a collaborative phase 3 challenge to address deficits observed in the phase 2 solutions. The collaborative model allowed contestants to work together to improve algorithm performance.
We compared the performance of the top AI algorithms from each phase against benchmarks including: (1) a commercially available, semi-automated segmentation software program (MIM Maestro, MIM Software) with and without human optimization of parameters; (2) the interobserver variation in manual segmentations between R.H.M. and 5 radiation oncologists in a previously published and publicly available,26,27 but similar external data set of 21 patients with lung cancer planned for RT (21 CT scans; median 178 images per scan; 3666 images in total; mean, roughly 226 images with tumor present); (3) intraobserver variation in the human expert performing the same segmentation task twice (independently, 3 months apart).
Furthermore, we validated algorithm performance and assessed for overfitting by applying the winning algorithms to the external, independent data set above. We estimated efficiency gains by comparing speed of expert manual segmentation vs the winning algorithms.
A total of 564 contestants from 62 countries registered for this challenge, and 34 (6%) submitted algorithms, including 244 unique submissions in phase 1 (mean, 8.4/participant), 164 in phase 2 (mean, 14.9/participant), and 180 in phase 3 (mean, 36/participant). Forty-five of these algorithms were submitted for the final scoring (phase 1, 29; phase 2, 11; and phase 3, 5). From these, we collected 10 independent, winning algorithms (eFigure 4 in the Supplement) developed by 9 unique winners.
Performance results for each phase are provided in eTable 3 in the Supplement; and Figure 2. For phase 1, the top 7 algorithms had average S scores on the holdout data set ranging from 0.15 to 0.38, and suboptimal performance using relative measures of error. The average S scores for phase 2 increased to 0.53 to 0.57, with a similar improvement in other performance metrics. In phase 3, performance of the top algorithm increased by an additional 9%. Combining the top 5 algorithms from phase 2 and phase 3 using an ensemble model (selected based on performance on the validation set; eMethods in the Supplement), yielded an additional 9% to 12% improvement in performance with a final S score reaching 0.68. The algorithms performed well for a variety of clinical situations and tumor locations (eFigures 1 and 5 in the Supplement).
The top contestants used a variety of approaches, including convolutional neural networks (CNNs), cluster growth, and random forest algorithms (eTable 4 in the Supplement). Solutions based on CNNs involved both custom and published architectures and frameworks to perform the tasks of object detection and localization (eg, Overfeat28), and/or segmentation (eg, SegNet29-31 and U-Net32). The latter were originally developed for the purpose of facial detection, biomedical image segmentation and road scene segmentation for autonomous vehicles research and adapted for the present task. The phase 3 algorithms produced segmentations at rates between 15 seconds/scan to 2 minutes/scan.
Examples of segmentations generated by human expert, commercially available software and contest algorithms are shown in Figure 1; and eFigure 1 in the Supplement. The phase 2 algorithms performed better than a commercially available, threshold-based autosegmentation software (eTable 3 in the Supplement) (Figure 2). The winning phase 3 algorithm and the ensemble models achieved scores within the interobserver variation and comparable to the interobserver mean between 5 other radiation oncologists and the expert from this study. Although the ensemble solution did not exceed the performance of the intraobserver benchmark (Figure 2 and Figure 3), approximately 75% of ensemble segmentations exceeded an S score of 0.60 (the lower threshold of intraobserver performance) which suggests that the contest produced algorithms capable of matching expert performance.
In addition, the performance of the contest’s top algorithms and the ensemble in the independent, external data set matched or exceeded their performance in the contest data set (eTable 3 in the Supplement). The mean time for the expert to perform manual segmentations was 8 minutes (range, 1-23 minutes), substantially longer than even the slowest algorithm.
The results of this study show that a combined approach that leverages crowd innovation to access computational expertise to develop AI algorithms coupled with human medical expert feedback can enable rapid development of multiple solutions for a complex medical task with performance comparable to human experts.
The ability to rapidly develop high-performing AI algorithms for tumor segmentation via a cost-effective crowd innovation approach has the potential to substantially improve the quality of oncologic care globally. Developing AI solutions for time-intensive tasks such as tumor segmentation can increase productivity and time with patients for busy clinicians by reducing computer-based work, and solve the known oncology workforce crisis (eg, number of trained radiation oncologists) in under-resourced health care systems worldwide.12 Artificially intelligent algorithms can also replicate and transfer expert-level knowledge for education, training, and/or quality assurance to raise the quality of global RT care. Providing quality assurance for RT trials is particularly important because variation in radiation planning even in highly structured protocols may be substantial enough to negatively impact outcomes and drive the results of trials toward the null.9 In addition, the ability to generate automatic tumor segmentations rapidly and accurately could revolutionize therapeutic response assessment in oncology in general, by allowing quantitative assessments of tumor imaging features during and after treatment, which may provide better predictive capability than traditional, manual, linear measurements (eg, RECIST).33,34
Deep learning methods like CNNs have been increasingly used for visual pattern recognition to automate important diagnostic tasks in medicine.19,21,24,35,36 For the therapeutic task of targeting lung tumors, the top algorithms produced by this challenge (Dice = 0.79 compared with human expert) performed comparably to algorithms used to detect/segment pathologic entities in prior studies, including invasive breast cancer (Dice = 0.76),24 and brain white matter hyperintensities (Dice = 0.79).35 Previous work to apply deep learning to RT by academia and private industry include automated AI segmentation for both tumor targets37,38 and normal organs.39-41 Our top algorithms compared favorably against these limited studies as well (eg, Dice = 0.81 for nasopharyngeal tumors).37 Furthermore, this study demonstrated that crowdsourced AI algorithms significantly outperform existing commercially-available, semi-automated segmentation tools, which have historically focused on atlas-based,42 PET-based,43 and single click region grow auto-segmentation44 approaches.
Successful crowd innovation contests start with proper design and methodology. These findings demonstrated that a multiphase challenge design can provide agility, including opportunities for recalibrating objectives to more closely align with the desired clinical output. We opted for phased contests with shorter durations, smaller prizes, and regular feedback because the objective was rapid prototyping of optimal solutions. This methodology helped us to quickly adapt the contest objectives, by obtaining a better understanding of how nondomain expert crowds could perform on this medical task. The timely feedback from the human expert contributed to the iterative improvement in performance. For example, the expert’s input regarding phase 1 algorithm performance was factored into the design of phase 2 to allow a seed point. The clinical expert was able to articulate that this would more closely resemble the clinical situation of RT planning where the clinician’s task is accurate targeting of a known lung tumor. With this input, the phase 2 solution performance improved by approximately 50%. Second, we demonstrated that using different designs for different phases of the contest opened opportunities for further performance gains. With phase 3, we transitioned from a large, crowd innovation competition, to a smaller, invitation-only collaborative contest, involving the top-performing contestants from phase 2. The design encouraged participants to fine-tune the most promising solutions produced in phase 2, with further improvement in performance.
Although past contests have leveraged crowds to produce AI solutions to problems in diagnostic oncology including in the 2017 Kaggle Bowl (early lung cancer detection in low-dose CT screening scans)45 and the 2016 DREAM Challenge (identifying breast cancer on digital mammograms)46,47 which also used a phased approach, the study reported here applied a multiphase crowd innovation approach with collaborative components to address a therapeutic problem. Whereas diagnostic challenges have a relatively simple gold standard in a pathologic diagnosis, in contrast, solving this therapeutic problem required quality volumetric segmentations of the tumor produced by an expert. Several other differences in contest design included cumulative duration (70 days in 3 phases for ours vs 90 days for Kaggle and 17 weeks for DREAM) and considerably smaller prize pool ($55 000 vs $1 000 000). Although on-demand crowd workers are now widely used in a range of tasks (eg, ride sharing, labor market platforms like UpWork/Freelancer), our research demonstrates that crowds can also augment and complement traditional academic research with considerable cost, time, and performance benefits. As demand for AI talent increases across the economy, and new AI methods rapidly evolve across a range of academic and industrial settings, this study demonstrates that a relatively low-cost, crowd innovation approach can be used to democratize the development of AI solutions in oncology beyond traditional academic and industrial circles, by enabling individual oncologists to access AI expertise, on demand to improve their own clinical and research practices.
The data sets used for this competition were relatively small compared with prior diagnostic radiology challenges (the Kaggle and DREAM challenge provided >1000 CTs and >600 000 mammograms, respectively), and the top algorithms likely underperform what would be observed with further training on a larger data set. However, the size of our data sets were comparable to those used in other recent applications of AI to RT, such as Google’s DeepMind’s efforts to automatically segment normal organs in the head and neck.41 Thus, AI can be successfully applied to solve problems in oncology even with limited data resources.
Furthermore, the production of the lung tumor segmentations relied on a single human expert, and the contest’s AI algorithms may have acquired the natural biases of that expert and generated segmentations representative of the training, experience, and judgment of 1 individual rather than objective ground truth (eFigure 6 in the Supplement). Nevertheless, replicating and delivering the manual skillset and experience of a given expert may still provide considerable value in therapeutic oncology.
This multifaceted crowd innovation challenge demonstrated that despite conservative constraints on contest duration and cost, it was possible to produce a diverse set of tumor segmentation AI algorithms that could replicate the abilities of a human expert and were faster. Using crowd innovation to generate clinically-relevant AI algorithms will allow sharing of scarce human expertise to under-resourced health care settings to improve the quality of cancer care globally.
Corresponding Author: Raymond H. Mak, MD, Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 75 Francis St, Boston, MA 02115 (firstname.lastname@example.org).
Accepted for Publication: January 7, 2019.
Published Online: April 18, 2019. doi:10.1001/jamaoncol.2019.0159
Open Access: This article is published under the JN-OA license and is free to read on the day of publication.
Author Contribution: Dr Endres had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Mak, Endres, Lakhani, and Guinan contributed equally to the work.
Study concept and design: Mak, Endres, Paik, Sergeev, Lakhani, Guinan.
Acquisition, analysis, or interpretation of data: Mak, Endres, Paik, Sergeev, Aerts, Williams, Guinan.
Drafting of the manuscript: Mak, Endres, Paik, Aerts.
Critical revision of the manuscript for important intellectual content: Mak, Endres, Paik, Sergeev, Williams, Lakhani, Guinan.
Statistical analysis: Endres, Sergeev.
Obtained funding: Paik, Aerts, Lakhani, Guinan.
Administrative, technical, or material support: Paik, Sergeev, Williams, Lakhani, Guinan.
Conflict of Interest Disclosures: Dr Mak reported personal fees from AstraZeneca and personal fees from NewRT outside the submitted work. Dr Endres reported grants from the Laura and John Arnold Foundation, grants from the Eric and Wendy Schmidt Foundation, grants from the Harvard Business School Kraft Precision Medicine Accelerator, and grants from the NASA Center of Excellence for Collaborative Innovation during the conduct of the study. Dr Paik reported grants from NASA Center of Excellence, grants from Eric and Wendy Schmidt Foundation, grants from Laura and John Arnold Foundation, grants from Harvard Business School Division of Research and Faculty Development, and grants from Harvard Business School Kraft Precision Medicine Accelerator during the conduct of the study. Dr Sergeev reported grants from The Laura and John Arnold Foundation during the conduct of the study. Dr Aerts reported grants from NCI during the conduct of the study; personal fees from Sphera, Genospace outside the submitted work. Dr Williams reported grants from Varian Medical Systems outside the submitted work. Dr Lakhani reported grants from Laura and John Arnold Foundation, grants from Kraft Family Foundation, grants from Schmidt Futures Foundation, grants from NASA, and grants from Division of Research & Faculty Development, HBS during the conduct of the study. Dr Guinan reported grants from Lucy and John Arnold Foundation and grants from NIH/NCATS during the conduct of the study.
Funding/Support: This study was funded by the Laura and John Arnold Foundation, Harvard Catalyst, The Harvard Clinical and Translational Science Center NIH UL1 TR001102, and the Division of Research and Faculty Development at Harvard Business School.
Role of the Funder/Sponsor: The Laura and John Arnold Foundation, Harvard Catalyst, The Harvard Clinical and Translational Science Center, and the Division of Research and Faculty Development at Harvard Business School had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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