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An Interview with Dr. Ann Gronowski, the President-Elect of the American Association for Clinical Chemistry

Q1. What are some of the key goals for AACC and its members in 2011?

The AACC has a number of key goals as it moves into 2011 including: developing ways to continue working with industry within the new AdvaMed guidelines; developing ways in which the AACC can collaborate more with other professional medical associations; increasing the recognition of translational science at our annual meeting; and continuing our global outreach both through the newly started Resource-limited countries project and through Lab Tests Online (LTO) and through the many translations of LTO and Clinical Chemistry journal articles. We are also seeking ways to improve the visibility of clinical chemists and increase the interaction of the medical community with laboratorians. Clinical chemists provide great value to the medical profession, but our expertise is often over looked and/or under-utilized.

Q2. How do you think government researchers and government-funded researchers could work more productively with the clinical chemistry community?

One of the ways this could be done is for researchers to seek the advice of clinical chemists and formally trained laboratorians early in the development of research projects. The National Cancer Institute (NCI) has taken a major step in advancing this concept by requiring that applicants for its recent Request For Applications (RFA) for the Clinical Proteomic Technologies for Cancer (CPTC) initiative provide evidence for expertise in laboratory clinical chemistry. Hopefully, this will result in better crafted proposals that have an improved chance of discovering and validating new diagnostic markers and tools that can translate into improved care for cancer patients. Together with the memorandum of understanding between AACC and the NCI, these actions provide ever greater recognition of the role of the clinical chemist in healthcare. In addition, it is important for the NCI and other government agencies to recognize that postdoctoral training programs in clinical chemistry train scientists in translational research. The programs continue to struggle with funding. It is my hope that once the importance of these translational scientists is recognized that they will get more government-funded support for training.

Q3. What are areas of interest and concern in the field of clinical chemistry?

There are many exciting emerging areas of clinical diagnostics. Personalized medicine, molecular diagnostics, metabolomics, and proteomics are just a few. Because the role of the clinical chemist continues to change and expand, the AACC hopes to continue to provide and expand educational programming in all of these areas. In addition, clinical chemists are extremely concerned with the quality delivery of healthcare in a cost effective manner. We are process orientated and as such are skilled in matters of lean design and quality metrics. These same principles can be applied to areas of therapeutics and treatment. Thus clinical chemists will face an expanding role as clinical consultants and translational scientists.

Q4. Moving forward, how do you see the Memorandum of Understanding between AACC and NCI (through the Office of Cancer Clinical Proteomics Research) progressing under your leadership? How can NCI and AACC facilitate further collaborations, e.g., training clinical chemists on quality metrics and standards developed by NCI-Clinical Proteomic Technologies for Cancer initiative (CPTC) investigators?

I hope that that the proteomics division will continue to partner with the NCI's CPTC initiative to develop educational programming both for proteomics researchers and for clinical chemists. These efforts could include: the development of workshops and educational events to improve the scientific community's awareness of research in clinical proteomics and the need for proteomic standards; the creation of educational materials that detail current standards and practices for proteomic technologies; the promotion of proteomic reagents and materials and their distribution to the clinical research community; and encouraging the development of publications and the dissemination of research results. Together, the goal of these efforts is to increase the translation of emerging proteomic technologies into clinical use.

Q5. What role can clinical chemists play in Quality Assurance (QA)/Quality Control (QC) measures for instrument platforms and validity of a clinical test?

Researchers involved in the discovery phase of biomarker development are often not familiar with formal QA/QC measures or with validation methods and guidelines; whereas, these practices are at the heart of the clinical chemistry profession. The involvement of clinical chemists in the verification phase of biomarker discovery will help to ensure that the test performance characteristics are specific, accurate and reproducible in the concentration range for the given biomarker. Another important area in which clinical chemists can make a contribution is in the assessment and management of pre-analytical variables such as sample handling. Clinical laboratorians not only have experience in rigorously evaluating the effects of broad variety of collection and processing issues, but they can also contribute in using this information to determine whether novel tests will be readily translatable to clinical practice.

Q6. In NCI's recent Request for Application (RFA-CA-10-016), one of the key aspects was the need for analytically validated platforms in the verification of protein content. As clinical chemists perform validated tests on a daily basis, how do you envision AACC members and CPTC researchers sharing knowledge and insights on developing analytically-validated protein assays with a possibility for diagnostic use?

Clinical chemists routinely validate analytic performance characteristics such as imprecision, bias, and the limits of quantification necessary to detect analytes in human blood. I envision clinical chemists helping to educate basic researchers on the importance of these performance characteristics and the proper way to assess these characteristics. In addition, the AACC provides programming on these types of performance validation methods. The methods of proteomics are far more complex and less defined than traditional clinical chemistry methods. Our profession will bring to the table many years of experience in this area and an appreciation of the technical complexities involved in verifying instrument performance and subsequently assay performance.

Q7. For multiplex proteomic assays, what is the input from clinical chemists in terms of proper analytical validation of a panel of biomarkers on newer platforms such as multiplex multiple reaction monitoring mass spectrometry (MRM-MS) and protein array technologies? How do you see innovativeness in development of mock 510(k) public review documents as a means to streamline the translation of regulatory science among the clinical chemistry community? [NCI developed mock 510(k) presubmissions in collaboration with the private sector, that were published in a special peer-reviewed issue of Clinical Chemistry (Feb. 2010) as a way to empower the medical community with the process on how to correctly design studies that address analytical and clinical questions asked by the FDA on multiplex, protein based assays- technologies poised to translate to a clinical setting in the coming years]

Although multiplex screening assays are already used by the clinical laboratory in applications such as neonatal screening for metabolic disorders, quantitative proteomics assays clearly present a new set of challenges. The recent submission and publication of mock 510(k)s has been a very important milestone because it has clarified many of the ground rules that will be important for researchers and demonstrated the types of requirements needed to carry a multiplex biomarker assay from discovery to an FDA-cleared or approved diagnostic test. Furthermore, it points out the need for a strong scientific/analytical foundation and clinical study design that is required for submission to the FDA. Beyond this initial regulatory approval, however, a strong partnership between clinical chemists and assay developers will also be important for determining the kinds of routine quality control measures that are required for the clinical implementation of multiplex proteomic assays that can be reliably used for patient care.

Q8. Because the level of risk to patient health determines the risk level of a diagnostic test, can you elaborate on how the clinical chemistry community defines and implements appropriate analytical and clinical validation criteria for analytes intended for moderate- or high-risk use, e.g., for cancer diagnosis?

The AACC supports the FDA's idea of employing a risk-based classification approach for determining the level of oversight for these assays, and we also believe that this classification should apply to the important ongoing work of creating new laboratory-developed tests (LDTs).

The FDA primarily considers the risks associated with IVD assays, specifically assessing the harm derived from an incorrect result (i.e. a false positive or false negative). From a clinical chemistry perspective, important components of this evaluation include the degree of change in an assay value that would affect clinical management, the total allowable error that is appropriate given this change, and the relationship of these values to the intra- and inter-individual variability. The clinical laboratory makes broad use of CLSI guidelines as a helpful starting place for clinical implementation once the initial FDA approval has been obtained.

Hopefully, changes in the definition and regulation of laboratory developed tests (LDTs) will not inhibit the development and use of important new assays. The AACC advocates a higher level of oversight by the FDA for LDTs that are only offered at a single laboratory, that have no external proficiency testing available, or that are marketed directly to consumers. By focusing oversight on these potentially problematic situations, clinical laboratories would still be in an excellent position to offer new tests to patients that have been carefully evaluated clinically prior to being deployed in a CLIA environment.

Q9. In terms of the development of new diagnostics and qualifying biomarker candidates, how should the community establish a comparative system to assess assay results from traditional immunoassays, if available, to those from next-generation analytical platforms such as multiplex multiple reaction monitoring mass spectrometry (MRM-MS) on the same analytes for the same intended use in order to establish the validity (or lack thereof) of the new approach?

The AACC along with the IFCC has many years of experience in developing reference standards and methods. There is a central role for multicenter consortia such as those being established through the CPTC for inter-lab and inter-method exchanges. As current studies progress, it will be strategically important to consider expanding the existing network of proteomics centers that are used to establish inter-laboratory reproducibility to include clinical laboratories led by clinical chemists with the necessary equipment and expertise.

Q10. Where do you see the clinical chemistry community going in the future in terms of the development of new diagnostic and therapeutic tests?

The clinical chemistry community finds itself in a unique position at the true translational research interface. On the one hand, our group takes responsibility for the delivery and interpretation of accurate laboratory measurements that are directly utilized in daily patient care. To carry out this task, a substantial body of expertise has been developed surrounding issues of sample handling, assay performance, analytical validation, and quality control. On the other hand, we are tasked with developing new assays that can advance our patient care mission into novel diagnostic areas. This means that many of our members are also involved in basic biomarker discovery and validation. These two facets of our field pinpoint the important benefit our members can provide to others in the research community, especially those who have identified novel markers, developed novel platforms, and discovered novel disease associations. We look forward to continuing to partner in these ways to facilitate the development and clinical implementation of a wide variety of diagnostic methods.