Achieving scientific consensus has been a challenging and contentious task since the dawn of the Scientific Revolution. Even as scientists have built up the body of experimental evidence, humans still have struggled to agree about what it means and what we should (or shouldn’t) do about it. Especially in the current era, stakeholders in industry, government, philanthropy, and science all have varying motives driving their scientific pursuits. These biases make it more difficult to agree on the policies and practices current evidence supports — and about which areas to investigate next. This crisis of consensus can compromise any evidence-based endeavor in medicine, including clinical and laboratory stewardship.
This problem underscores the need all stakeholder groups have for an open-access, decentralized data repository that thoroughly abstracts data from published evidence, enables streamlined peer review and voting on inclusion/exclusion in meta-analyses, displays aggregate results, and highlights differences in interpretation of the data among stakeholders.
Now, a group of volunteer clinicians, data scientists, students, and web developers are working to develop MetaCensus: the first open-access data repository built to host data to be peer-reviewed and meta-analyzed to catalyze consensus in science.
The Case of DPYD Genotype-Guided Chemotherapy
The serious consequences of a lack of agreement about scientific evidence was visible in the controversy over the use of DPYD genotype-guided chemotherapy for cancer patients. Fluoropyrimidines are a widely utilized chemotherapeutic in cancer care with well-known toxicity risks. Carriers of pathogenic DPYD gene variants treated with fluoropyrimidines are reported to have a 25.6 times greater risk of treatment-related death than patients with non-pathogenic DPYD variants (1).
In North America, routine preemptive DPYD genotyping is not currently considered standard of care. For example, pretreatment DPYD testing is not promoted by the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), or U.S. Food and Drug Administration (FDA). Meanwhile, the European Medicines Agency (EMA), the French National Agency for the Safety of Medicines and Health Products, and the Medicines and Healthcare Products Regulatory Agency (United Kingdom) recommend preemptive DPYD/DPD testing for patients treated with fluoropyrimidines (2–4).
Such international discord on what actions might be considered appropriate for DPYD testing in routine patient care decisions compounds the problem in the U.S.. Patient harm from fluoropyrimidine use without DPYD testing has led to lawsuits, including one against Oregon Health and Science University (OHSU), which paid a $1 million settlement to the widow of a patient with DPD deficiency fatally affected by fluoropyrimidine toxicity. OHSU also agreed to hold seminars to educate clinicians on the risks associated with DPD deficiency, how to identify and treat severe fluoropyrimidine toxicity, and, where appropriate, how to order DPYD testing (5,6).
In August 2022, Dana-Farber Cancer Institute — a National Cancer Institute (NCI) - designated cancer center, the highest federal rating a cancer center can achieve — began encouraging routine DPYD testing, even though practice guideline-producing entities like the NCCN (which controls NCI-cancer center designation) and the FDA state there isn't adequate evidence to recommend pretreatment screening (7). Moffitt Cancer Center, Levine Cancer Institute, University of Chicago, Dartmouth, Cleveland Clinic, Yale, and University of Michigan have also implemented DPYD testing.
Many factors contribute to the discord on whether to implement DPYD testing. Still, one central issue is the absence of a shared data resource where all individual stakeholder groups (regulatory bodies, and basic scientists, clinicians, insurers, guideline-producing associations) provide their input on the current strengths, limitations, and conclusions drawn from available data. This limits the ability of each individual stakeholder group to compare other’s data and practices to their own. Such comparisons are essential for deliberation and an attempt at consensus to be catalyzed through meta-analysis and multicriteria decision analysis (MCDA) (8).
How The MetaCensus Network Can Help
MetaCensus is built on a distributed ledger that employs blockchain technology to render data open and free for the public to review. It also structures a peer review voting mechanism that encourages voters to critically analyze the data, provide feedback, and vote on its inclusion in meta-analyses hosted on the blockchain. Any interested party can build web applications that provide free access to the data they use from MetaCensus. This can help solve the challenges society faces with most scientific journals not offering open-access publishing (9).
A blockchain network based on the Ethereum platform has been created using the Proof of Authority consensus method, which removes the cryptocurrency component inherent in blockchains and ensures that only credentialed and vetted actors that are a part of the MetaCensus network can contribute to the security and stability of the network.
Blockchain networks store the state of the network at a defined frequency, and those states are “mined” (verified) as a “block” which gets added to its canonical history. Smart contracts are immutable code that live on the network and drive the network’s purpose.
For MetaCensus, there are eight smart contracts with functions and data types that store and run the logic to maintain scientific consensus for any scientific discipline, or community, which chooses to store their standard of consensus on the network. These functions cannot be changed, only interacted with, and are used to ensure standardized logic to reach the goals, rules, and consensus needed. Additionally, the data structures built into the smart contracts store the data abstracted from results in peer-reviewed publications, maintaining an up-to-date consensus.
All of this is driven by the community of members that are a part of a scientific discipline. Voting members of the community take part in peer review and voting for or against pending data being included in any meta-analysis. Nonvoting members can only access the data and voting results.
Pending data items include: approving a paper to be part of the standard consensus model or not, changing the way the consensus model is calculated, adding and removing members and voters, or changing the threshold consensus percent to pass a pending data item.
Inherently, the data and code in blockchain networks are available for anyone to view and use. However, in an effort to simplify and streamline access, a website is being created for users to easily interact with the network without knowing coding software required for blockchain interaction.
The smart contract structure enables the community to review how any member has voted longitudinally. This structure also allows the community to track how a member’s votes compare with other members within their same stakeholder group’s expertise versus those of others and perform MCDA on the results. Comparisons could include clinicians, biostatisticians, payers, regulators, or a guideline-producing association.
The indelible ledger inherent with blockchain ensures that a record of prior voting histories (collective and individual) is available for review and analysis as the landscape of available evidence changes. As individual papers amass peer reviews, this may hold the potential to generate a new publication score that is more informative than a journal’s impact factor, number of citations, or other measures of significance.
Conclusion
MetaCensus aims to catalyze consensus by providing an open-access repository to scientific information that is peer-reviewed by credentialed volunteer subject matter expert communities. Importantly, it makes this data free and accessible to all, empowering anyone who wishes to investigate and learn.
As consensus is cultivated, we hope that a better understanding of factions raised by various stakeholder domains will inform the community on what next steps in research should be prioritized in grant funding. We also believe it will enable guideline-producing groups to leverage data to develop their recommendations, improve how insurers efficiently review data to weigh coverage decisions, and enable clinical groups to use the data for web applications in clinical decision support.
The MetaCensus team eagerly welcomes all feedback, considerations, and volunteer contributions of data or effort that advances our mission.
Ryan S. Nelson, PharmD, is the medical director of precision medicine at ARUP Laboratories in Salt Lake City, Utah. Email: [email protected]
Erik R. Forsman, BS Ch.E, is a senior data consultant at ARUP Laboratories in Salt Lake City, Utah. Email: [email protected]
Gwendolyn A. McMillin, PhD, DABCC (CC,TC), FAACC, is a scientific and medical director, and professor, at the ARUP Institute for Clinical and Experimental Pathology, and in the department of pathology, University of Utah School of Medicine, in Salt Lake City, Utah. Email: [email protected]
References
- Sharma BB, Rai K, Blunt H, et al. Pathogenic DPYD variants and treatment-related mortality in patients receiving fluoropyrimidine chemotherapy: A systematic review and meta-analysis. Oncologist 2021; doi: 10.1002/onco.13967
- NHS England. Pharmacogenomic testing for DYPD polymorphisms with fluoropyrimidine therapies. https://www.england.nhs.uk/publication/clinical-commissioning-urgent-policy-statement-pharmacogenomic-testing-for-dpyd-polymorphisms-with-fluoropyrimidine-therapies/ (Accessed November 2023).
- U.K. Chemotherapy Board. Personalised medicine approach for fluoropyrimidine-based therapies. https://www.theacp.org.uk/userfiles/file/resources/dpd-testing-ukcb-july-2020-updated.pdf (Accessed November 2023).
- European Medicines Agency. Fluorouracil and fluorouracil related substances (capecitabine, tegafur, and flucytosine) containing medicinal products. https://www.ema.europa.eu/en/medicines/human/referrals/fluorouracil-fluorouracil-related-substances-capecitabine-tegafur-flucytosine-containing-medicinal (Accessed November 2023).
- The Oregonian. OHSU to pay $1 million, promises change to settle lawsuit from widow of cancer patient. https://www.oregonlive.com/health/2022/05/ohsu-to-pay-1-million-promises-change-to-settle-lawsuit-from-widow-of-cancer-patient.html (Accessed November 2023).
- The Oregonian. OHSU chemotherapy killed cancer patient, suit claims. https://www.oregonlive.com/news/2019/12/ohsu-chemotherapy-killed-cancer-patient-suit-claims.html (Accessed November 2023).
- Precision Medicine Online. Cancer centers nudge oncologists toward DPYD testing as PGx supporters push for guidelines change. https://www.precisionmedicineonline.com/regulatory-news-fda-approvals/cancer-centers-nudge-oncologists-toward-dpyd-testing-pgx-supporters (Accessed November 2023).
- Gongora-Salazar P, Rocks S, Fahr P, et al. The use of multicriteria decision analysis to support decision making in healthcare: An updated systematic literature review. Value Health 2023; doi: 10.1016/j.jval.2022.11.007
- The Guardian. Is the staggeringly profitable business of scientific publishing bad for science? https://www.theguardian.com/science/2017/jun/27/profitable-business-scientific-publishing-bad-for-science (Accessed November 2023).