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.

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.

Semi-automated fact-checking of nucleotide sequence reagents in biomedical research publications: The Seek & Blastn tool.

Nucleotide sequence reagents are verifiable experimental reagents in biomedical publications, because their sequence identities can be independently verified and compared with associated text descriptors. We have previously reported that incorrectly identified nucleotide sequence reagents are characteristic of highly similar human gene knockdown studies, some of which have been retracted from the literature on account of possible research fraud. Because of the throughput limitations of manual verification of nucleotide sequences, we developed a semi-automated fact checking tool, Seek & Blastn, to verify the targeting or non-targeting status of published nucleotide sequence reagents. From previously described and unknown corpora of 48 and 155 publications, respectively, Seek & Blastn correctly extracted 304/342 (88.9%) and 1066/1522 (70.0%) nucleotide sequences and a predicted targeting/ non-targeting status. Seek & Blastn correctly predicted the targeting/ non-targeting status of 293/304 (96.4%) and 988/1066 (92.7%) of the correctly extracted nucleotide sequences. A total of 38/39 (97.4%) or 31/79 (39.2%) Seek & Blastn predictions of incorrect nucleotide sequence reagent use were correct in the two literature corpora. Combined Seek & Blastn and manual analyses identified a list of 91 misidentified nucleotide sequence reagents, which could be built upon through future studies. In summary, incorrect nucleotide sequence reagents represent an under-recognized source of error within the biomedical literature, and fact checking tools such as Seek & Blastn may help to identify papers and manuscripts affected by these errors.

The Possibility of Systematic Research Fraud Targeting Under-Studied Human Genes: Causes, Consequences, and Potential Solutions.

A major reason for biomarker failure is the selection of candidate biomarkers based on inaccurate or incorrect published results. Incorrect research results leading to the selection of unproductive biomarker candidates are largely considered to stem from unintentional research errors. The additional possibility that biomarker research may be actively misdirected by research fraud has been given comparatively little consideration. This review discusses what we believe to be a new threat to biomarker research, namely, the possible systematic production of fraudulent gene knockdown studies that target under-studied human genes. We describe how fraudulent papers may be produced in series by paper mills using what we have described as a 'theme and variations' model, which could also be considered a form of salami slicing. We describe features of these single-gene knockdown publications that may allow them to evade detection by journal editors, peer reviewers, and readers. We then propose a number of approaches to facilitate their detection, including improved awareness of the features of publications constructed in series, broader requirements to post submitted manuscripts to preprint servers, and the use of semi-automated literature screening tools. These approaches may collectively improve the detection of fraudulent studies that might otherwise impede future biomarker research.