Paper mill challenges: past, present, and future.

Paper mills are fraudulent organizations that make money by writing fake manuscripts and offering authorship slots for sale to academic customers. Mill activity differs in scale to individual academic misconduct: many thousands of fake paper mill manuscripts have been successfully published in peer-reviewed journals. Despite this, paper mill activity is still relatively unrecognized outside the publishing industry. We discuss what is known about paper mill operations and how publishers, independent organizations, and individuals are working to prevent and detect mill activity. Research readers can also have a part to play in paper mill detection, and we provide detail on what to look out for.

Misspellings or "miscellings"-Non-verifiable and unknown cell lines in cancer research publications.

Reproducible laboratory research relies on correctly identified reagents. We have previously described gene research papers with wrongly identified nucleotide sequence(s), including papers studying miR-145. Manually verifying reagent identities in 36 recent miR-145 papers found that 56% and 17% of papers described misidentified nucleotide sequences and cell lines, respectively. We also found 5 cell line identifiers in miR-145 papers with misidentified nucleotide sequences and cell lines, and 18 cell line identifiers published elsewhere, that did not represent indexed human cell lines. These 23 identifiers were described as non-verifiable (NV), as their identities were unclear. Studying 420 papers that mentioned 8 NV identifier(s) found 235 papers (56%) that referred to 7 identifiers (BGC-803, BSG-803, BSG-823, GSE-1, HGC-7901, HGC-803, and MGC-823) as independent cell lines. We could not find any publications describing how these cell lines were established. Six cell lines were sourced from cell line repositories with externally accessible online catalogs, but these cell lines were not indexed as claimed. Some papers also stated that short tandem repeat (STR) profiles had been generated for three cell lines, yet no STR profiles could be identified. In summary, as NV cell lines represent new challenges to research integrity and reproducibility, further investigations are required to clarify their status and identities.

An Approach to Evaluate the Costs and Outputs of Academic Biobanks.

Academic biobanks commonly report sustainability challenges, which may be exacerbated by a lack of information on biobank value. To better understand the costs and supported outputs that contribute to biobank value, we developed a systematic, generalizable methodology to determine biobank inputs and publications arising from biobank-supported research. We then tested this in a small cohort (n = 12) of academic cancer biobanks in New South Wales, Australia. A proforma was developed to capture monetary and in-kind biobank costing data from biobank managers and publicly available sources. Participating biobanks were grouped and compared according to the following two classifications: open- versus restricted-access and high versus low total annual costs. Our methodology provides a feasible approach for capturing comprehensive costing data for a defined period. Characterization of biobanks using this approach showed that median total costs, as well as median staffing and in-kind costs, were comparable for open- and restricted-access biobanks, as were the quantity and journal impact metrics of supported publications. High- and low-cost biobanks supported similar median numbers of publications; however, high-cost biobanks supported publications with higher median journal impact factor and Altmetric scores. Overall, 9 of 10 biobanks had higher Field-Weighted Citation Impact scores than the global average for similar publications. This is the first tested, generalizable approach to analyze the costs and publications arising from biobank-supported research. By determining explicit cost and output data, academic biobanks, funders, and policymakers can engage in or support informed redirection of resourcing and/or benchmark setting with the aim of improving biobank support of research.

Applying Findable, Accessible, Interoperable, and Reusable Principles to Biospecimens and Biobanks.

The importance of stimulating greater sharing of data for use and reuse in health research is widely recognized. To this end, the findable, accessible, interoperable, and reusable (FAIR) principles for data have been developed and widely accepted in the research community. Research biospecimens are a resource that leads to much of this health research data but are also a form of data. Therefore, the FAIR principles should apply to biospecimens. Nevertheless, there is a widespread problem of not sharing biospecimen resources that is clearly visible within the research arena. The impacts of this are likely to include diversion of precious research funds into compiling duplicate biospecimen cohorts, detraction from research productivity as researchers compete for and create duplicate resources, and deterrence of attempts to assess research reproducibility. This article explores some of the barriers that may limit availability of FAIR biospecimens. These barriers relate to the type of biospecimen collections and the characteristics of the custodians that influence their intention and interest in sharing. Barriers also relate to the ethical, legal, and social issues concerning collections, the research context of the collections, and cost and expertise involved in repurposing collections to enable sharing. Several solutions to increase sharing are identified. Some have recently been implemented, including enhancing biospecimen locators with tools to guide researchers and facilitating transfer of research collections to centralized biobank infrastructures at the conclusion of projects. New proposed solutions include improving search capabilities within publication databases, and introduction of evidence-based justifications for all new collections into peer-reviewed grant competition processes. It is recognized that there are both scientific factors and practical reasons that can impose limits to sharing biospecimens. However, funding availability, productivity, and progress in health research all stand to benefit from improved sharing of research biospecimen collections.

Verification of nucleotide sequence reagent identities in original publications in high impact factor cancer research journals.

Human gene research studies that describe wrongly identified nucleotide sequence reagents have been mostly identified in journals of low to moderate impact factor, where unreliable findings could be considered to have limited influence on future research. This study examined whether papers describing wrongly identified nucleotide sequences are also published in high-impact-factor cancer research journals. We manually verified nucleotide sequence identities in original Molecular Cancer articles published in 2014, 2016, 2018, and 2020, including nucleotide sequence reagents that were claimed to target circRNAs. Using keywords identified in some 2018 and 2020 Molecular Cancer papers, we also verified nucleotide sequence identities in 2020 Oncogene papers that studied miRNA(s) and/or circRNA(s). Overall, 3.8% (251/6647) and 4.0% (47/1165) nucleotide sequences that were verified in Molecular Cancer and Oncogene papers, respectively, were found to be wrongly identified. Wrongly identified nucleotide sequences were distributed across 18% (91/500) original Molecular Cancer papers, including 38% (31/82) Molecular Cancer papers from 2020, and 40% (21/52) selected Oncogene papers from 2020. Original papers with wrongly identified nucleotide sequences were therefore unexpectedly frequent in two high-impact-factor cancer research journals, highlighting the risks of employing journal impact factors or citations as proxies for research quality.

Biobanking and research quality: think locally, act globally.

Although biobanks can support research across geographic and governance boundaries, biomedical researchers consistently describe preferences for either collaborating with local biobanks or establishing their own biobanks. This article summarizes the potential research impacts of local biobank use and suggests how descriptions of biospecimen provenance can be improved in research publications.

Protection of the human gene research literature from contract cheating organizations known as research paper mills.

Human gene research generates new biology insights with translational potential, yet few studies have considered the health of the human gene literature. The accessibility of human genes for targeted research, combined with unreasonable publication pressures and recent developments in scholarly publishing, may have created a market for low-quality or fraudulent human gene research articles, including articles produced by contract cheating organizations known as paper mills. This review summarises the evidence that paper mills contribute to the human gene research literature at scale and outlines why targeted gene research may be particularly vulnerable to systematic research fraud. To raise awareness of targeted gene research from paper mills, we highlight features of problematic manuscripts and publications that can be detected by gene researchers and/or journal staff. As improved awareness and detection could drive the further evolution of paper mill-supported publications, we also propose changes to academic publishing to more effectively deter and correct problematic publications at scale. In summary, the threat of paper mill-supported gene research highlights the need for all researchers to approach the literature with a more critical mindset, and demand publications that are underpinned by plausible research justifications, rigorous experiments and fully transparent reporting.

Is the future of peer review automated?

The rising rate of preprints and publications, combined with persistent inadequate reporting practices and problems with study design and execution, have strained the traditional peer review system. Automated screening tools could potentially enhance peer review by helping authors, journal editors, and reviewers to identify beneficial practices and common problems in preprints or submitted manuscripts. Tools can screen many papers quickly, and may be particularly helpful in assessing compliance with journal policies and with straightforward items in reporting guidelines. However, existing tools cannot understand or interpret the paper in the context of the scientific literature. Tools cannot yet determine whether the methods used are suitable to answer the research question, or whether the data support the authors' conclusions. Editors and peer reviewers are essential for assessing journal fit and the overall quality of a paper, including the experimental design, the soundness of the study's conclusions, potential impact and innovation. Automated screening tools cannot replace peer review, but may aid authors, reviewers, and editors in improving scientific papers. Strategies for responsible use of automated tools in peer review may include setting performance criteria for tools, transparently reporting tool performance and use, and training users to interpret reports.

The Availability of Human Biospecimens to Support Biomarker Research.

Preserved biospecimens held in biobank inventories and clinical archives are important resources for biomarker research. Recent advances in technologies have led to an increase in use of clinical archives in particular, in order to study retrospective cohorts and to generate data relevant to tissue biomarkers. This raises the question of whether the current sizes of biobank inventories are appropriate to meet the demands of biomarker research. This commentary discusses this question by considering data concerning overall biobank and biospecimen numbers to estimate current biospecimen supply and use. The data suggests that biospecimen supply exceeds current demand. Therefore, it may be important for individual biobanks to reassess the targets for their inventories, consider culling unused portions of these inventories, and shift resources towards providing prospective custom biobanking services.

Identification of human gene research articles with wrongly identified nucleotide sequences.

Nucleotide sequence reagents underpin molecular techniques that have been applied across hundreds of thousands of publications. We have previously reported wrongly identified nucleotide sequence reagents in human research publications and described a semi-automated screening tool Seek & Blastn to fact-check their claimed status. We applied Seek & Blastn to screen >11,700 publications across five literature corpora, including all original publications in Gene from 2007 to 2018 and all original open-access publications in Oncology Reports from 2014 to 2018. After manually checking Seek & Blastn outputs for >3,400 human research articles, we identified 712 articles across 78 journals that described at least one wrongly identified nucleotide sequence. Verifying the claimed identities of >13,700 sequences highlighted 1,535 wrongly identified sequences, most of which were claimed targeting reagents for the analysis of 365 human protein-coding genes and 120 non-coding RNAs. The 712 problematic articles have received >17,000 citations, including citations by human clinical trials. Given our estimate that approximately one-quarter of problematic articles may misinform the future development of human therapies, urgent measures are required to address unreliable gene research articles.

In vitro and in vivo drug screens of tumor cells identify novel therapies for high-risk child cancer.

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.

What Do Biomedical Researchers Want from Biobanks? Results of an Online Survey.

Aims: The purpose of biobanking is to provide biospecimens and associated data to researchers, yet the perspectives of biobank research users have been under-investigated. This study aimed to ascertain biobank research users' needs and opinions about biobanking services. Methods: An online survey was developed, which requested information about researcher demographics, localities of biobanks accessed, methods of sourcing biospecimens, and opinions on topics including but not limited to, application processes, data availability, access fees, and return of research results. There were 27 multiple choice/check box questions, 4 questions with a 10-point Likert scale, and 8 questions with provision for further comment. A web link for the survey was distributed to researchers in late 2019/early 2020 in four Australian states: New South Wales, Victoria, Western Australia, and South Australia. Results: Respondents were generally satisfied with biobank application processes and the fit for purpose of received biospecimens/data. Nonetheless, most researchers (n = 61/99, 62%) reported creating their own collections owing to gaps in sample availability and a perceived increase in efficiency. Most accessed biobanks (n = 58/74, 78%) were in close proximity (local or intrastate) to the researcher. Most researchers had limited the scope of their research owing to difficulty of obtaining biospecimens (n = 55/86, 64%) and/or data (n = 52/85, 60%), with the top three responses for additional types of data required being "more long term follow up data," "more clinical data," and "more linked government data." The top influence to use a particular biobank was cost, and the most frequently suggested improvement was reduced direct "cost of obtaining biospecimens." Conclusion: Biobanks that do not meet the needs of their end-users are unlikely to be optimally utilized or sustainable. This survey provides valuable insights to guide biobanks and other stakeholders, such as developing marketing and client engagement plans to encourage local research users and discouraging the creation of unnecessary new collections.

"No Country Bureaucratised its way to Excellence": A Content Analysis of Comments on a Petition to Streamline Australian Research Ethics and Governance Processes.

We created a petition for a national inquiry into the Australian system of research ethics and governance, to inform the politicians about the problems with the existing system. We analyzed the reasons that signatories offered for why signing the petition was important to them. A total of 409 comments (by 805 signatories) focused on five major themes: (1) views on previous changes to the system of research ethics and governance; (2) drawbacks of the existing system; (3) suggested changes to the system; (4) anticipated impacts of changing the system; and (5) miscellaneous/other comments. Comments ranged from several words to over 400 words in length, and most often focused on the procedural aspects, and commented on theme 2: drawbacks of the existing system.

How Many Health Research Biobanks Are There?

Introduction: It is important for many research stakeholders to know how many biobanks exist. There are several potential data sources that might be expected to provide biobank numbers, such as institutions, research funders, and literature databases (e.g., PubMed), but in practice this information is rarely available and is hard to find. However, the maturation of several online health research biobank locators (also known as directories and catalogs) that relate to 12 countries and/or states has now provided some initial data to address the question of how many health research biobanks exist in relation to population size. Methods: We have analyzed four biobank locators: the Biobanking and Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium directory, the Canadian Tissue Repository Network locator, the Australian New South Wales Australia Health Pathology locator, and the UK Clinical Research Collaboration Tissue Directory. Results: We conclude that across these locators, and in those regions with potential for high research capacity as indicated by comparable gross domestic products, there are 11-30 health research biobanks/million population (2 large biobanks with >1000 samples and a further 9-28 are medium-small biobanks). Conclusion: Many locators were established primarily to increase utilization of biobanks. However, locators may be more useful in tracking the numbers of biobanks and in assisting funders and institutions to monitor research strategy and prevent unnecessary duplication of biobank resources.

Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer.

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of ß-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.

Vignettes to Illustrate the Value of Tumor Biobanks in Cancer Research in Canada.

Background: Tumor biobanks are a common research infrastructure. As a collection of biospecimens and annotated data collected to support a multitude of research projects, biobanks facilitate access to materials that are the critical fuel for the generation of data in up to 40% of cancer research publications. However, quantifying how to measure biobanks' impact and their value on the field of cancer research discoveries and findings, has not been well elucidated. Methods: We have used a qualitative case study approach to illustrate the impact of tumor biobanks. We assessed the impact of three research studies published between 2010 and 2012 that required easily accessible "classic" biobanks. Each study utilized preassembled collections of tumor biospecimens with associated patient outcomes data at the outset of the research project. We compared the resulting journal impact factor, altmetric and field-weighted citation impact factor scores for each article to a set of six "benchmark" articles that represent cancer research and treatment discoveries from the same time period and two sentinel scientific discovery articles. Results: We developed a value model using a literature search and design-thinking methodologies to illustrate the contributions of these "classic" model biobanks to these research studies. Assessment of the three example articles supported by biobanks demonstrates that the output can have impact that is comparable to the impact of a set of benchmark articles describing milestones in the field of cancer research and cancer care. Conclusions: These case studies illustrate the value of the sustained investment of funds, planning, time, and effort on the part of the biobanks before the conduct of the research study to be able to ultimately support high-value research. The "value" model will enable further discussion around impact and may be useful in better delineating qualitative metrics of biobank value in the future.