Published online on September 29, 21012

Link to the original blog:

http://www.sciclips.com/sciclips/blogArticle.do?id=1022&blog=How%20to%20Identify%20Clinically%20Successful%20Biomarkers?

How to Identify Clinically Successful Biomarkers?

New developments in research mean that many more biomarkers are now being discovered than ever before. However, there is currently no well-defined pathway linking biomarker research to health services research. The result is that while new biomarkers are constantly being identified, for many diseases there are not enough biomarkers that are of proven usefulness in patient care today (source UK National Institute for Health Research (NIHR)(1). This may be largely true due to the fact that the discovery, selection and validation of biomarkers for clinical diagnostics applications may be more complex and challenging than we ever thought. The primary goal of biomarker discovery, for any diseases or disorders, is to facilitate the development of clinically viable biomarkers that can be used for diagnostics or prognostics applications. Finding clinically reliable and robust biomarker/s with high diagnostic accuracy in a significant number of patients who are affected with a specific disease, irrespective of the geographical barriers and other confounding factors, can be complex and convoluted, may be even more trickier than therapeutic drug target discovery and validation processes. In our earlier blog we have critically analyzed potential complexities associated with current biomarker discovery approaches (2). According to our scientific analysis, thousands of biomarkers that are currently being reported may not be true biomarkers of the target disease, rather it may be a complex mixture of biomarkers, which may include target disease specific biomarker as well as biomarkers or biomolecules associated with other diseases, infections, gender, race/ethnic backgrounds, geographic-environmental factors, psychiatric condition/diseases and nutritional factors. Therefore, an ideal clinical biomarker discovery platform, which can lead to the development of reliable and robust clinical diagnostics assays, should adopt an integrated approach that consists of comprehensive understanding of patients phenotypic, genetic and socio-environmental characteristics as well as biological and functional relevance of all biomolecules. Significant modifications in patient selection procedures, biomarker discovery technologies, clinical assay development and biomarker validation protocols may be desirable in developing clinical biomarkers with high diagnostic accuracy and cost-effective for patients/health care providers. In order to achieve these goals, we propose two models (Fig. 1) for the discovery, selection and validation of clinically viable biomarkers, an exception to this model will be infectious diseases or genetic/hereditary diseases or disorders, which can be detected using infectious organism specific or gene specific diagnostic assays respectively. However, for the development of infectious disease associated drug-efficacy or companion diagnostic biomarkers the proposed model may be effective. Irrespective of the fact that our proposed model is acceptable or unacceptable to basic and clinical research communities, innovative approaches are warranted for the discovery of clinical biomarkers, with faster bench to clinics timeline, to provide high quality and efficient patient care. In contrast, if we continue with the strategic and technological approaches that are currently being adopted for biomarker discovery and validation, most likely, it 1|Page
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may take several years to find clinically viable biomarker/s for complex diseases like cancer or neurodegenerative or autoimmune or other human diseases. Moreover, biomarker discovery strategies that may result in the development of high-cost clinical diagnostic assays or products may not be suitable neither for reducing mortality and morbidity from diseases nor for reducing health care costs, most of the hospitals and patients will not be able to afford costly life-saving products. Thus, the decisive goal of clinical biomarker discovery should be intended for developing high quality and lowcost disease detection/monitoring assays with high diagnostic accuracy. A. Top-down strategy for the discovery of clinical biomarkers

1. Collaborative biomarker discovery Systematic and productive multidisciplinary global scientific collaborations will be one of the key factors in the success of the proposed model. The Biomarkers Consortium by the Foundation for National Institutes of Health (3) and the International Cancer Biomarker Consortium at Fred Hutchinson Cancer Research Center are few examples for this kind of collaborations. However, these conventional form of collaborations need to be revised for the proposed strategies for the development of clinical biomarkers. Indeed, highly organized large-scale global collaborations may potentially lead to the identification of clinical biomarkers specific for a country or a region or an ethnic group, due to the dependency of disease manifestation on genetic or geneenvironment or other factors, may lead to the development of personalized diagnostics products. Probably, this collaborative biomarker discovery approach may lead to the identification of a panel of biomarkers, with dependency on patient specific characteristics, having high predictive values in majority of patients using a specific or a specific combination of biomarker/s identified.

2. Patient selection and patient derived sample collection for biomarker discovery Current approaches in biomarker discovery that involve individual laboratories or a small group of laboratories may not be adequate to find clinically successful biomarkers in the immediate future. The biomarkers that are identified by individual laboratories may result in unsuccessful outcome in clinical trials. This is primarily due to the fact these studies use limited number of patient samples without indepth understanding of patients genetic/non-genetic characteristics, and the limitations of the technologies used in biomarker discovery, uniform strategies need to be implemented, which can be addressed through bottom-up biomarker discovery strategy explained in the next section. Thus, for developing highly efficient and cost-effective clinical diagnostic assays the most important criteria are the selection of patients from various geographical areas, adoption of uniform sample collection procedures and implementation of common biomarker discovery technologies at the beginning of the discovery phase. Utilization of STARD (Standards for the Reporting of Diagnostic accuracy studies) (4) components, recommendations for tumor marker prognostic studies (REMARK) (5, 6,7) reporting guidelines and randomized controlled trials recommendations of the CONSORT statement (8, 9), 2|Page
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Fig. 1: Top-down approach for the identification and characterization of clinical biomarkers 3|Page
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modified to incorporate genetic and non-genetic factors aligned with multicenter globalized screening procedures, can be adopted at the early stage of biomarker discovery. Patients characteristics such as gender, ethnicity, geographical location, prevalence of target diseases, incidence of other diseases in patients geographical location, patients disease history, food habits etc. should be recorded along with the biomarker identification data. In fact, US FDA has addressed the effect of spectrum bias, which lacks complete spectrum of patient characteristics, in the diagnostic accuracy by recommending tests using patients or specimens from entire range of disease states, confounding diseases or disorders and from different demographic groups (9). Adoption of this recommendation from the beginning of biomarker identification and selection procedures may significantly improve the success rate in finding clinical biomarkers with high diagnostic accuracy. With respect to biospecimen collection and handling procedures for biomarker studies, standardized protocols are being considered (10). 3. Technologies used for biomarker discovery The technologies or methods used for biomarker discovery play an integral role in finding successful clinical biomarkers. The technologies should be preferably 1) robust, cost-effective and easy to adopt in various laboratories worldwide, less expertise dependent, low technology dependent variability, high reproducibility, less patient sample handling steps, low sample loss, transferability across laboratories and amendable for generating comprehensive and meaningful data. Immunohistochemistry (e.g. tissue arrays), in situ hybridization, genomics technologies based on next generation sequencing and antibody arrays are the most promising technologies that may well suitable for large scale multi-geographical biomarker identification efforts. Emerging technologies like proteomics may have to be considered very cautiously since these technologies are more complex, not as robust as other technologies, and may have several pitfalls and limitations (12,13,14,15,16,17,18,19,20). A snapshot of various technologies used in cancer biomarker discovery (source: Sciclips Cancer Biomarker Database (21) is shown in Fig. 2. As evidenced from this preliminary data analysis, immunohistochemistry and molecular diagnostic (genomics, miRNA, qRT-PCR, SNPs) methods are the most widely used technologies used for initial identification of cancer biomarkers. Immunoassays (ELISA, protein/antibody arrays) come next, followed by proteomics and metabolomics.

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4. Biomarker identification and validation Information of biomarkers identified from different geographical locations with all other patient and geographical characteristics can be pooled together and can be analyzed using statistical methods, mathematical simulations and bioinformatics. This approach may help in identifying a panel of exploratory biomarkers, which can be further analyzed in a second set of patients from different geographical locations 5. Clinical evaluation of biomarkers in patients The clinical utility of candidate biomarkers can be validated using a phased approach (22,23) in patients from various geographical locations or a specific region, depending on the biomarker selected.

6. Development of clinical diagnostic assays Suitable clinical diagnostic assays can be developed based on the type of biomarkers identified, e.g. protein biomarkers (immunoassays or diagnostic imaging), nucleic acid markers, including epigenetic biomarker (molecular diagnostic detection methods such as PCR or next generation sequencing or diagnostic imaging) or metabolomic biomarkers (immunoassays or mass spectrometry or diagnostic imaging). B. Bottom-up strategy for the discovery of clinical biomarkers In bottom-up clinical biomarker strategy, which may not require organized large-scale global studies, data generated from individual laboratories worldwide will be utilized for the identification and clinical validation of clinically useful biomarkers. A flow chart for this approach is shown in Fig. 3. The key factors in this approach are 1) implementation of a standard patient sample collection and recording procedures where all the patients genetic and non-genetic characteristics, ethnicity, geographical disease prevalence or other relevant epidemiological and population genetics information will be recorded, 2) adoption of a standard biomarker discovery technology to avoid discrepancies in data, multiple biomarker discovery technologies can be adopted if standardized biomarker confirmation and validation procedures are recommended and 3) implementation of standardized bioinformatics, statistical and mathematical analysis methods. Therefore, implantation of standardized procedures/ protocols for biomarker discovery/validation and data analysis/interpretation strategies is inevitable for the generation of clinically successful biomarkers from individual academic or industrial laboratories. Although several guidelines such as WHO (World Health Organization) standards for the diagnosis of myocardial infarction and American Rheumatology guidelines for the diagnosis of lupus or rheumatoid arthritis are currently available, these standards need to be revisited to accommodate strategies and tools that are may lead to the successful discovery of clinical biomarkers and diagnostic assays. 5|Page
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Fig. 3: Bottom-up approach for the identification and characterization of clinical biomarkers 6|Page
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Note: This scientific blog is a contribution from Sciclips Consultancy team (link: http://www.sciclips.com/sciclips/consultancy.do). References References are hyperlinked to respective abstracts or full articles. Please click the reference numbers to the citation details Related blogs: Strategies for Rational and Personalized Cancer Biomarker Discovery (link:http://www.sciclips.com/sciclips/blogArticle.do?id=1021&blog=Strategies%20for%20Rational %20and%20Personalized%20Cancer%20Biomarker%20Discovery). Cancer Theranostics Potential Applications of Cancer Biomarker Database (link:http://www.sciclips.com/sciclips/blogArticle.do?id=1017&blog=Cancer%20Theranostics%20%2 0-%20Potential%20Applications%20of%20Cancer%20Biomarker%20Database). Potential Use of Drug Response-Efficacy Biomarkers for Predicting Life-Threatening Disease Causing Side Effects of Therapeutic Drugs (link:http://www.sciclips.com/sciclips/blogArticle.do?id=1020&blog=Potential%20Use%20of%20Dr ug%20Response-Efficacy%20Biomarkers%20for%20Predicting%20LifeThreatening%20Disease%20Causing%20Side%20Effects%20of%20Therapeutic%20Drugs). Related tools: Comprehensive cancer biomarker database with companion diagnostics pathway (link: http://www.sciclips.com/sciclips/diagnostic-prognostic-cancer-biomarker-main.do).

Published online on September 29, 21012

Link to the original blog:

http://www.sciclips.com/sciclips/blogArticle.do?id=1022&blog=How%20to%20Identify%20Clinicall y%20Successful%20Biomarkers?

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