Pathologists and clinical laboratories will play a key role in collecting the data needed to create a person’s digital twin
Digital twins is a promising new technology that is making a big impact in healthcare. This development is significant because clinical laboratory test results will be among the most important sets of data to go into the creation of a patient’s “digital twin.”
A digital twin is defined by IBM as “a virtual representation of an object or system designed to reflect a physical object accurately. It spans the object’s lifecycle, is updated from real-time data, and uses simulation, machine learning, and reasoning to help make decisions.”
“We define a digital twin for healthcare as a virtual representation of a person which allows dynamic simulation of potential treatment strategy, monitoring and prediction of health trajectory, and early intervention and prevention, based on multi-scale modeling of multi-modal data such as clinical, genetic, molecular, environmental, and social factors, etc.,” wrote the authors of a review article published in NPJ Digital Medicine titled, “Digital Twins for Health: A Scoping Review.”
“The concept of digital twin for health (DT4H) holds great promise to revolutionize the entire healthcare system, including management and delivery, disease treatment and prevention, and health well-being maintenance, ultimately improving human life,” wrote study lead Eva Katsoulakis, MD (above), clinical informaticist and radiation oncologist at Tampa General Hospital in Florida, et al, in a review article she and her team published in NPJ Digital Medicine. Clinical laboratory test data will be a key element in the creation of a patient’s digital twin. (Photo copyright: Tampa General Hospital.)
Development of Digital Twins
Something akin to digital twins was first used in 1960 at NASA when replicas of spacecrafts currently on a mission in space were duplicated and studied on Earth. In 1991, Michael Grieves introduced the concept to manufacturing while at University of Michigan’s College of Engineering. The technology was later coined “digital twins” by John Vickers, a principal technologist in advanced manufacturing at NASA in 2010, IBM noted.
The increased use of digital twins in healthcare has brought some brilliant advancements. Examples, as reported by Computer Weekly, include:
Surgery and treatment: Boston Children’s Hospital uses digital twins to examine the complexities of heart procedures in reference to oxygen, blood flow, and valve pressure. Real-time analysis helps with surgeries and treatments, allowing clear visualization at all angles.
Metabolic analysis to tackle kidney failures: Digital twins are being used in Singapore to “Replicate metabolic fluxes to predict chronic kidney disease in type 2 diabetes mellitus.” Doctors there hope to curb the spike of chronic kidney disease found in type 2 diabetes mellitus. Their country has seen cases double in the last 40 years.
Bacterial predictions, E. coli: Bacteria behavior is being analyzed in computational simulations as part of a Simulating Microbial Systems (SMS) program. Run by the US Defense Advanced Research Projects Agency, the “SMS seeks interdisciplinary, comprehensive, and integrated workflows to generate unknown parameters from new data to inform computational models that can predict E. coli.”
Full body data: Precisely personalized care is the goal of European Virtual Human Twins Initiative, a project from the European Commission. The group creates digital twins and updates them with an individual’s personal conditions and health information that shifts as they age, keeping prevention as a focal point.
Respiratory viral pathogens: The complexities and variety of causes behind respiratory infections makes it an ideal area for digital twins. Its use in hospital ICUs can help doctors consider pneumonia treatment outlooks and develop plans for spread of infection.
Pharmaceuticals: Many pharma companies are opting to use digital twins since drug development is highly expensive and animal testing does not always provide clear data compared to human testing. Examples include Orion Pharma, which paired with AstraZeneca and Bayer to create digital twins that “capture genetic and molecular interactions that causally drive clinical and physiological outcomes.” Immunology company, Sanofi, also is using digital twins as “an essential first step to improve efficacy and safety.”
Future of Digital Twins in Healthcare
While digital twin development within healthcare is still in early stages, it promises to pioneer much change.
“When you have this model, you can personalize with certain features, certain anatomy, then you can try things. In heart surgery, you can’t try 20 different things, you only have one shot,” Ellen Kuhl PhD, professor of engineering and bioengineering at Stanford University, told Computer Weekly.
As technology advances and personalized healthcare continues to trend, it is likely digital twins will have a long-term place in medical practices. Astute clinical laboratory professionals will watch the expansion of this trend, since lab data will play such a key role in its development.
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.
“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.
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.
Once thought to be separate components, the new model of a contiguous mesentery could lead to new medical laboratory tools for diagnosing and treating digestive diseases such as Crohn’s and colorectal cancer
For more than a century, pathology professionals have treated the network of tissue folds surrounding the human digestive system, known as the mesentery, as separate entities. However, new research indicates the mesentery is in fact a single, continuous organ and therefore reverses that thinking. This could impact the way pathologists and medical laboratories currently perform diagnostics and testing of digestive diseases.
American Society of Clinical Pathology study cites better pay and lack of skills as main barriers to recruiting MTs, CLSs, and MLTs
Staffing shortages of medical technologists (MT) continue to be a significant problem for clinical laboratories across America. Moreover, the vacancy rates of qualified clinical laboratory scientists required to properly staff medical laboratories are increasing. These findings were released recently by the American Society for Clinical Pathology (ASCP).
At the management level, it was reported that recruiters are finding it particularly hard to fill supervisory positions in Histology Laboratories and Blood Banks. Further, experts predict that Chemistry, Immunology and Histology labs will suffer most over the next five years as Baby Boomers retire in ever-increasing numbers.
