Preanalytical sample handling protocols can advance personalized medicine and science

Basic research and industry adoption of standard protocols and tools for preanalytical sample handling are necessary to advance personalized medicine and science

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A Brooklyn surgeon and renowned journalist named Dr. Atul Gawande has been recently traveling nationwide promoting a very simple idea to reduce medical errors in hospitals: Checklists. His idea, proffered in a book titled, The Checklist Manifesto: How to Get Things Right, is, in the simplest of terms, that in a world of increasing complexities, even the experts need basic guidelines to manage complicated procedures.

Gawande visited places such as Boeing and observed how pilots relied on checklists to navigate not just daily routines, but also emergencies. Commissioned by the World Health Organization, Gawande and his research team put together simple, two-minute lists to make explicit the protocols surgeons already thought they knew. The checklists consisted of some basic questions: "Were there antibiotics on hand?" "Is there blood available?" They also required surgeons to introduce themselves before procedures.

After rolling out the checklists in eight hospitals, Gawande discovered that complications resulting from surgeries dropped dramatically—in many cases, by a third. Deaths were fewer as well. By making explicit some basic protocols and standards, Gawande and his team's simple "checklist" saved money, time and in some instances, even lives.

What Gawande realized was that with all the advanced education, training and high technology that accompanies the practice of medicine today, it's the human brain that touches or connects it all. Although at most times very reliable, brains can fail at the simplest tasks. Brains get interrupted. Brains get distracted. Brains get confused. Brains make mistakes.

We can apply many of these lessons to simple scientific procedures as well. We have made great advances in biomedical sample analysis, patient diagnosis, disease research and drug discovery. We live in a world filled with the promise of personalized medicine. Yet, for all this progress, we still lack some very basic protocols and standards for some of the most critical passages of research: biomedical sample handling before analysis.

Although biospecimens such as cells, serum, blood, tissue, urine or saliva are routinely collected to support patient diagnosis, disease research, and clinical trials, sample handing protocols vary widely and sometimes do not even exist. Indeed, preanalytical sample handling protocols—if any—are often inherited and treated more like cooking instructions than scientific protocols.

Preanalytical sample handling covers the spectrum from collection and preparation to storage of molecules and tissues. The methods are often developed in an ad hoc fashion or adapted from older methods without much questioning or quality control, and can vary greatly from user to user, lab to lab and clinic to clinic.

This is particularly noteworthy because errors in preanalytical sample handling can greatly impact the outcome of scientific experiments and clinical trials, not to mention influence the treatment of patients and increase the cost of basic and clinical research and healthcare.

Astoundingly, it is estimated that preanalytical variables account for up to 70 percent of laboratory errors. These variables occur anytime from when a test is ordered by a physician until the sample is ready for analysis, and can occur as a result of improper tube handling or inadequate temperature control of the sample. For patients and physicians, errors at the preanalytical phase could mean inaccurate test results.

For basic science and drug research and development, errors in preanalytical sample handling can have dire consequences as well. Biospecimens are extremely vulnerable to environmental and biological stresses introduced by routine collection, processing, storage and transport procedures prior to analysis. These often overlooked preanalytical sample handling variables may permanently change the integrity and molecular profile of the biospecimen.

And get ready for this: Data variability caused by differences in the way human and animal samples are acquired and processed is considered to be the major roadblock in post-genomic basic and clinical research, according to the National Cancer Institute's (NCI) Office of Biorepositories and Biospecimen Research (OBBR).

Benchtop sample processing and temperature control, for example, is an integral part of most biomedical sample preparation and storage; yet techniques for sample management and temperature control remain in the "Middle Ages," employing decades-old tools for cooling, freezing, snap-freezing and thawing. This opens the door for minor to major variability in test results across users and laboratories; hence, standard tools and protocols are needed now.

Take the ice bucket. A very common method of sample collection and cooling, the ice bucket isn't exactly a sophisticated workstation. It can be messy, unorganized and unreliable. Scientific protocols consist of a long list of complex steps, many of which involve manipulating the contents of differing subsets of tubes. Even one instance of error through the loss of a label or disorganization can alter the outcome of an experiment or assay, rendering the results meaningless and costing time and money.

As in medicine, there's also the risk of interruptions. Executing complex assays requires extreme focus on the part of the researcher. But in busy laboratories, the possibilities for interruption are great—as are mistakes. It's not uncommon for researchers to make a mistake in the order of sample or tube manipulation sequence, again jeopardizing the integrity of the result. Errors also occur when samples are contaminated or lost, which can happen easily when beads of melted ice that have formed near the tube cap enter the tube when it's opened.

Without proper management of preanalytical variables, resulting variables in data may be misinterpreted as disease- or drug-related findings and add significant cost or lead to misdiagnosis or inappropriate treatment. New attention to this very basic issue is needed, particularly with the increasing dependence on biomarkers in drug discovery and development and disease treatment. Additionally, the number of large study collaborations that include multiple sites and laboratories around the world is growing, and companies are increasingly outsourcing drug discovery and development efforts to other countries.

Government and scientific bodies worldwide are beginning to work toward common standard operating procedures for preanalytical sample handling. In January 2009, the European Union launched a research project aimed at expanding the use of in vitro diagnostics by creating new standards for the collection, handling and processing of blood, tissue, tumor and other sample materials. Dubbed the SPIDIA project (Standardization and improvement of generic preanalytical tools and procedures for in vitro diagnostics), the project is set to run for four years at a cost of more than $16.6 million.

In particular, the importance to the field of molecular diagnostics is clear. But the integrity and quality of the biomedical sample being analyzed is paramount. If the molecular profile of a target molecule is changed because of improper or differential sample handling or processing, or storage of the sample, the sample then become useless for analysis.

In promoting the initiative, Arnd Hoeveler, head of the health biotechnology unit in the Directorate General for Research at the European Commission, stated, "Far too many differing sample processing methods, which then lead to different results, are still being used … This variance hampers the comparability and reproducibility of results and reduces the meaningfulness of the analyses. More standardized guidelines and quality assurance schemes will help to introduce new and better diagnostic methods, which will benefit all European patients."

Other efforts are under way as well. The OBBR initiated the Biospecimen Research Network (BRN) in early 2006 to consider how variables in the collection, processing and storage of human biospecimens affects molecular analysis. Specifically, the goal of the BRN is to sponsor, conduct, and collaborate on studies that evaluate the effects of these preanalytical variables on the outcome of genomic and proteomic studies conducted for clinical diagnosis and cancer research purposes.

In sum, preanalytical sample handling is an often overlooked, very basic, often boring but very essential part of science. Basic research and industry adoption of standard protocols and tools for preanalytical sample handling are necessary to advance personalized medicine and science.

Dr. Rolf Ehrhardt is the founder and CEO of BioCision LLC in Mill Valley, Calif. He has more than 20 years of experience in basic research, drug discovery and development and translational science, working for Intermune Inc., Corgentech (now Anesiva), BioSeek and Protein Design Labs (now PDL BioPharma Inc.). Ehrhardt was a Deutsche Forschungsgemeinschaft and Fogarty Fellow at the National Institutes of Health, where his focus was on mucosal immunology and inflammatory bowel disease. He earned his medical and doctoral degrees with distinction from the Technical University of Munich in Germany. Ehrhardt has authored more than 40 peer-reviewed publications and holds multiple patents.

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