Mar 26, 2018 | Compliance, Legal, and Malpractice, Laboratory Management and Operations, Laboratory Operations, Laboratory Pathology, Laboratory Testing, Management & Operations, News From Dark Daily
As the public gains awareness of the role clinical laboratories play in modern healthcare, increased engagement and understanding of the technology underlying many of these advances could create risk for labs without transparent reporting protocols to both patients and the public
In recent years, consumers have continually raised the bar in their expectation of quality when they interact with the healthcare system. Not only do patients expect providers—including clinical laboratories and anatomic pathology groups—to improve regularly over time, but the public has even less tolerance for medical errors of any type. Thus, a recent NPR story is one more warning to the medical laboratory profession that it should be devoting resources and effort to improving quality.
Today’s healthcare consumers and patients are more educated about and involved in the care process than ever before. While the exact science and skills may not interest the general public, the technologies underpinning much of the shift toward personalized medicine (AKA, precision medicine) are the same technologies that created the always-connected, digital lifestyles seen around the world.
With this, comes a level of scrutiny and questioning from the public that clinical laboratories or anatomic pathology groups would not have experienced even just a decade ago.
Mounting Scrutiny of Medical Laboratories and Healthcare Professionals
A recent segment on NPR’s “All Things Considered” highlighted this trend and questioned the quality control standards behind many of the procedures powering current testing. The segment also questioned the impact quality control has on the quality of biobanks used to research and create future technologies and tests.
Pathologist Richard Friedberg, PhD, Medical Director of Baystate Reference Laboratories and former president of the College of American Pathologists, told NPR, “We need to be sure that the stuff [doctors and researchers are] looking at is valid, accurate, reliable, and reproducible … If it’s garbage in, it’s garbage out.”
The story highlights improved standards and guidelines surrounding immunohistochemical (IHC) HER2 tests in the early 2000s. In 2007, The New York Times questioned the reliability of the tests, based on studies presented to the American Society of Clinical Oncology the week prior.
In response, the American Society of Clinical Oncology and the College of American Pathologists released guideline recommendations outlining the exact standards required to reduce assay variation and ensure that data produced is accurate and reproducible. NPR’s coverage claims this is the only test with such strict guidelines.
“I don’t think physicians think this way about their entire medical system,” Carolyn Compton, PhD, CMO of the National Biomarker Development Alliance, CMO of the Complex Adaptive Systems Initiative, and professor of Life Sciences at Arizona State University, told NPR. “I don’t see how we’re going to get precision medicine at the end of the day when everything under the hood is so imprecise.”
When data and previous research powers much of the innovation taking place across the modern healthcare landscape, the accuracy of said data would seem critical. Yet, without standards in place, there’s not always safeties by which to verify sample integrity and other critical concerns.
Late last year, Dark Daily reported on a study published in PLOS ONE from Radboud University in the Netherlands questioning the accuracy of more than 30,000 published scientific studies that contained misidentified or contaminated cell lines. Guidelines, such as those created for IHR and FISH HER2 testing, provide standards intended to prevent such issues from occurring or detecting them when they do occur.
Quality versus Quantity: A Gamble Worth Taking?
Apart from challenges with healthcare reform and the regulatory landscape surrounding precision medicine, medical laboratories also must struggle with the challenges of gleaning and maintaining useful, accurate information from an ever-growing trove of data produced by analyzers and assays.
Yet, these mediocre datasets include the results of tests that carried a potentially significant impact on patient lives. In the first two weeks of February alone, both the St. Louis Post-Dispatch and The Telegraph published stories related to erroneous testing related to cancer and the potential impact on the clinical laboratories involved and the patients tested.
Increased coverage shows that the world is watching what goes on in medical laboratories, hospitals, and data centers as healthcare continues to evolve. Clinical laboratories must move forward with this in mind or risk pushback and questioning from the public. Transparency regarding standards, and reporting information to patients surrounding testing or concerns, might effectively address this rising trend.
“We are moving faster and faster and faster as this whole precision medicine train is moving down the track,” Tim Allen, MD, Laboratory Director at the University of Texas Medical Branch Department of Laboratory Services, told NPR. “I suspect standardization of these things is going to become a reality much quicker than I would have expected even a few years ago.”
That quality control issues in anatomic pathology are considered newsworthy by no less than NPR is a sign of increased public attention to the quality of lab testing. The story was written to educate the public about the gap that exists in the quality control of anatomic pathology testing. All of this is consistent with the trend for providers to be transparent and report their quality metrics to the public, including patients.
—Jon Stone
Related Information:
Hormone Receptor Testing Volume 1: Investigation and Findings Commission of Inquiry on Hormone Receptor Testing
Precision Medical Treatments Have a Quality Control Problem
HER2 TESTS: How Do We Choose?
Cancer Drug May Elude Many Women Who Need It
American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer
Impact of Electronic Health Record Systems on Information Integrity: Quality and Safety Implications
His Doctor Said It Was Cancer. It Wasn’t. But the Lab Mix-Up News Came Too Late.
Up to 60,000 Cancer Test Results May Have to Be Reviewed After Women Wrongly Given the All-Clear
Over 30,000 Published Studies Could Be Wrong Due to Contaminated Cells
Netherlands University Researchers Question Validity of More Than 30,000 Published Scientific Studies; Findings Have Implications for Medical Laboratories
Dec 27, 2017 | Compliance, Legal, and Malpractice, Laboratory News, Laboratory Pathology, Laboratory Testing
Radboud University researchers fear oncology, molecular biology, pharmacology, and other cell-centric medical research efforts are at risk due to verification that at least 30,000 studies published in 33,000 scientific journals included data derived from misidentified or contaminated cell lines
Many research findings that underpin the science behind various diagnostic technologies used regularly by clinical laboratories and anatomic pathology groups may not be valid. This is because a large number of published studies may have used misidentified or contaminated cell lines.
Biomedical scientists have known for a long time that many research papers exist containing reports on the wrong cells due to cell line misidentification. And yet, few studies have measured the true scope of the problem. Until now. Researchers at Radboud University in the Netherlands have determined that this problem may have influenced the findings of thousands of published research studies and upon which many other research studies were conducted.
Because clinical laboratories and anatomic pathology groups use assays and diagnostic tests that are developed as a result of these research studies, identifying how many published papers have inaccurate findings that cannot be duplicated would affect how and when it is appropriate for physicians to order certain medical laboratory tests and rely on the results.
Additionally, cancer research is based on cell line studies as well. Thus, it may prove necessary to restudy existing published findings and revise them as appropriate. In turn, these new findings might change how and when some cancer tests are ordered and the results interpreted.
Identifying Corrupted Published Data
Radboud researchers Serge P. J. M. Horbach, a doctoral student, and Willem Halffman, PhD, Associate Professor, Philosophy and Science Studies, used the Web of Science database to track down any scientific articles based on “known misidentified cell lines as listed by the International Cell Line Authentication Committee’s (ICLAC) Register of Misidentified Cell Lines,” according to an article in ScienceAlert.
“We considered a reference to this original article as a good proxy for the usage of a cell line,” the researchers noted in their study published in the journal PLOS ONE. “Since typically the original papers are focused on reporting the establishment of the cell line only.”
They focused on misidentified cell lines that were caused by HeLa cells, also known as “immortalized cells.” HeLa cells have been used in scientific research for decades. They were the first mass-producible cells that could be used in vitro, making them highly desirable for biomedical research.
However, the process of creating immortalized cells involves mutation, during which contamination can be introduced by other cells. Immortalized cells can be identified as one type of cell when in fact they are actually another type of cell.
Research scientists have been aware of this problem for about as long as immortalized cells have been in use. They attempt to take it into account when completing their analyses, though not always successfully.
The Radboud researchers found 32,655 records of primary literature based on contaminated cell lines. They then cross-referenced the ICLAC Register of Misidentified Cell Lines with a range of databases to determine if articles were available for each of the 451 cell lines listed on Table One of the ICLAC Register.
The databases they used included the:
With this information, they further researched published articles in the Web of Science database using cell line identifiers. They noted both primary literature and any citation report entries for each cell line.
The researchers noted in their published study, “As we only searched for cell lines known to be misidentified, this constitutes a conservative estimate of the scale of contamination in the primary literature. Moreover, to avoid false positives, we excluded several cell lines, such as the ones with non-unique identifiers or the cell lines for which verified stock is still in circulation.”
Their estimate for secondary contaminated literature based off primary articles is larger still. “In total, we can conservatively estimate the citations to the primary contaminated primary literature at over 500,000, excluding self-citations,” the authors noted in their PLOS ONE article. “Thereby leaving traces in a substantial share of the biomedical literature.” They concluded, “… the amount of research potentially building on false grounds remains worrisome.”
Impact of Contaminated Cell Lines on Research, Clinical Laboratory Communities
Many of the assays and diagnostic tests performed by clinical laboratories and pathology groups were developed using cell line research. Should further scrutiny into the ability to duplicate and verify study findings fail to produce positive outcomes, it might call into question the validity and appropriate use of these tests.
For the research community, these findings represent yet another call to promote accountability and define standards for verifying authenticity of cell lines to further strengthen research findings.
The Radboud researchers ranked the number of contaminated articles they discovered by research area. Top affected areas include:
- Oncology
- Molecular Biology
- Pharmacology
- Cell Biology
- Immunology
The distribution of contaminated primary literature over the research areas as defined by Web of Science. Only the 25 most affected research areas are included. (Graphic copyright: PLOS ONE.)
Addressing the Problem of Cell Line Contamination and Misidentification
Adapting the ever-growing body of published medical literature to reflect the known misidentifications, as well as the possibility of invalid results, will be a major undertaking. Ultimately, resolving this problem could require changes to practices and procedures currently used by research facilities and medical laboratories.
While the cost to authenticate cell lines adds to the bottom line of research projects, the money spent on research that becomes invalidated by misidentified cell lines is far greater.
In a 2015 Retraction Watch article, Leonard P. Freeman, PhD, President, Global Biological Standards Institute, notes, “An NIH RePORT search identified 9,000 active projects using cell lines, totaling $3.7 billion. Required use of authentication techniques would affect over $900 million in research dollars annually.”
Additionally, failure to adapt authentication as a part of standard operations brings other consequences. “A 2004 survey reported that just one-third of laboratories authenticate their cell lines,” Freeman noted. “10 years later, a Sigma-Aldrich survey found that only 37% of respondents ‘validate the purity and identity before first use’ of cell lines. Understanding the existing barriers that prevent implementation of universal cell authentication is central to changing this sad state of affairs.”
Mixed Recommendations for Fixing Inaccurate Published Studies
Of course, none of this will change the vast body of archived literature that might contain errors due to misidentification. Recommendations for addressing this aspect of the problem vary. The Radboud study authors suggest posting notes on any previously published articles stating that misidentified cell lines were used.
However, in a STAT article, Ivan Oransky, MD, and Adam Marcus, Managing Editor, Gastroenterology and Endoscopy News, co-founders of Retraction Watch, recommend more severe measures. “When we polled readers of Retraction Watch last December about the issue, 55% said journals should correct papers known to describe contaminated or misidentified cell lines, and more than 40% said retraction was the right choice.”
Thanks to the Radboud study, as cell lines continue to power the innovations of modern biomedical research, concerns will surely increase surrounding cell-line authentication and research findings. For pathology groups and medical laboratories, staying abreast of these developments will work to ensure data validity and reduce reputation and liability concerns.
—Jon Stone
Related Information:
Over 30,000 Published Studies Could Be Wrong Due to Contaminated Cells
The Ghosts of HeLa: How Cell Line Misidentification Contaminates the Scientific Literature
The Economics of Reproducibility in Preclinical Research
Crosscontamination of Cells in Culture
Cell Authentication Survey Shows Little Progress in a Decade
Apparent HeLa Cell Contamination of Human Heteroploid Cell Lines
Some 30,000 Biomedical Publications Report on Misidentified Cells
Cell Line Misidentification: The Beginning of the End
Fixing Problems with Cell Lines
Thousands of Studies Used the Wrong Cells, and Journals Are Doing Nothing
We’re Wasting a Lot of Research Funding Using the Wrong Cell Lines. Here’s One Thing We Can Do
Misidentified and Contaminated Cell Lines Lead to Faulty Cancer Science, Experts Say
STR Analysis for Cell Line Authentication Gaining Traction in Research Community
