Authors: Amy K. Wagner, MD Gwendolyn Sowa, MD, PhD
Management
Affiliations: From the Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pennsylvania.
COMMENTARY
Correspondence: All correspondence and requests for reprints should be addressed to: Amy K. Wagner, MD, University of Pittsburgh, 3471 Fifth Ave, Suite 202 Pittsburgh, PA 15213.
Rehabilomics Research A Model for Translational Rehabilitation and Comparative Effectiveness Rehabilitation Research
Disclosures: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.
0894-9115/14/9310-0913 American Journal of Physical Medicine & Rehabilitation Copyright * 2014 by Lippincott Williams & Wilkins DOI: 10.1097/PHM.0000000000000114
ABSTRACT Wagner AK, Sowa G: Rehabilomics research: a model for translational rehabilitation and comparative effectiveness rehabilitation research. Am J Phys Med Rehabil 2014;93:913Y916. Key Words: Rehabilomics Research, Rehabilitation, Comparative Effectiveness Research, Evidence-Based Medicine, Biomarkers, Personalized Medicine
EXECUTIVE SUMMARY & There exists a particular need for increased personalization in the care of rehabilitation patients because of physical, cognitive, emotional, and social/ environmental heterogeneity. & Rehabilomics research can address this need through examining the full range of individual biologic characteristics that may contribute to heterogeneity, impact recovery, and guide treatment decisions. & It is recommended that additional support be provided to multidisciplinary groups to examine biologic measures contributing to outcome and treatment effects while maintaining the patient-centric focus on function that is unique to rehabilitation care and research. Research in the field of physical medicine and rehabilitation is unique with regard to the broad populations that are served and the wide-ranging individual variability in impairments, functional limitations, and treatment responses. It is well recognized that rehabilitation does not lend itself to a singular Bprotocolized[ plan of care or therapy, and the evaluation of each person must include an individualized assessment of physical, cognitive, emotional, and social systems, each of which uniquely interacts to affect recovery.1 Traditionally, rehabilitation practitioners customize individual rehabilitation protocols for their patients on the basis of the specific needs, supports, and barriers identified, making protocol standardization a challenge. This is particularly problematic when attempting to validate treatment efficacy for specific interventions or clinical decision algorithms. Further, heterogeneity in clinical presentation and treatment response, within the multifaceted aspect of participation, including resumption of personal and societal roles and goals, also creates challenges for rehabilitation researchers to answer pertinent questions regarding rehabilitation treatment optimization and efficacy with traditional study designs.2 However, outcome variability may
www.ajpmr.com
Rehabilomics Research and Comparative Effectiveness Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
913
be attributable to genetic and other biological variation that patients bring to recovery and the unique response to each person’s care and environment. Thus, an individual’s biologic profile could be used to tailor treatments that optimize outcomes. Other fields (e.g., oncology) have embraced this Bomics[based theranostic approach to individualize care on the basis of specific results generated to guide these treatments.3 Beyond the traditional genetic approaches, additional modifiable biologic measures applicable to rehabilitation may help to inform diagnostics, prognostics, as well as treatment approaches and responses. The difficulties with conducting rigorous clinical trials, while preserving the principles of personalized care, can be addressed in many ways by the integration of a Rehabilomics research model. Rehabilomics is a concept developed by the authors’ field of expertise to describe such a personalized approach to rehabilitation research,4 where the full range of individual biologic characteristics is examined to determine which characteristics impact recovery and the nature of this impact. Essentially, this biologically grounded concept provides an B-omic[ overlay to the scientific study of rehabilitation processes and outcomes, personalizing the approach to rehabilitation and aimed at optimizing individual recovery. The World Health Organization’s International Classification of Functioning Disability and Health is central to defining and operationalizing a formula for characterizing function across multiple domains.5 The International Classification of Functioning Disability and Health model specifies common constructs and language for assessing function in clinical care and rehabilitation research that, along with innovative technology linking biorelevant symptoms to both biomarker and outcomes, is central to the Rehabilomics concept. Importantly, pairing biomarkers with a rehabilitation-focused rigorous research design and data collection tools is critical to derive meaningful information about rehabilitation as a health strategy. Therefore, it is recommended that the International Classification of Functioning Disability and Health model be incorporated into future rehabilitationrelevant biomarker identification to ensure relevance to function and patient-centered outcomes. Rehabilomics is a biomarker-focused framework from which to study population-specific mechanisms of recovery,6 and this concept can be used to describe personalized approaches to rehabilitation care and research. A broad range of individual biologic characteristics can be examined, leading to personalized approaches to rehabilitation aimed
914
Wagner and Sowa
at optimizing individual recovery. Rehabilomics can be a helpful tool to bridge the rapidly expanding field of biologics in the context of rehabilitation care. It is recommended that support be provided to facilitate the development of Rehabilomics approaches in various areas of rehabilitation medicine to maximally capitalize on the capacity of biologic outcome measures while maintaining the patientcentric focus on function. As the field of biologics advances and complement traditional approaches, Rehabilomics research programs may emerge as an important tool for successful translation of these agents to clinical care and may allow physical medicine and rehabilitation to be on the cutting edge that shapes this area of biomedical research and care.7 However, more work is needed to identify appropriate markers and understand the sensitivity of these markers to condition progression, recovery, and treatment response to fully incorporate Rehabilomics principles in biologics testing and research design. When developing a portfolio of funding priorities for a contemporary comparative effectiveness research program focused on the area of Rehabilomics, one must consider multiple issues including the following: (1) the definition and operationalization of the term biomarker, which may include genetics, epigenetics, transcriptomics, metabolomics, proteomics, cognitive and/or physical performance metrics, imaging and physiologic measures, as well as interaction with social and environmental exposures, (2) infrastructure needed for large-scale longitudinal studies that are needed to characterize chronic conditions/recovery as well as chronic care interventions, (3) the barriers and opportunities for person-centered care among populations with disabilities, and (4) developing the appropriate research infrastructure and expertise to conduct definitive treatment studies. To achieve these goals, it may be relevant for research programs to leverage National Institutes of Health-funded Clinical and Translational Science Awards (CTSA) site resources for biomarker identification and exploration efforts using state-ofthe-art platforms. In addition, it may be relevant to leverage existing populations, such as what is captured by the National Institute for Disability and Rehabilitation Research (NIDRR) model system databases, for capacity-building initiatives to support larger-scale Rehabilomics investigations. Capacity building through telerehabilitation and point-of-care assay platforms development is needed to support clinical and outcomes data collection to use in combination with rehabilitation-relevant biomarker panels. A biomarker is an objectively measured characteristic that is an indicator of normal biologic
Am. J. Phys. Med. Rehabil. & Vol. 93, No. 10, October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
processes, pathogenic processes, or response to a therapeutic intervention.8 A valuable biomarker should theoretically meet at least 2 criteria: (1) it should be sensitive to the changes of the condition, and (2) it should be specific to a characteristic of the condition. Biomarkers identified in blood and other biofluids are commonly considered in most areas of biomarkers research. However, a range of biomarkers beyond those observed in biofluids can be considered within the context of Rehabilomics research and can include radiographic endpoints, physiologic markers, and even cognitive performance and participations measures. The Institute of Medicine’s Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Diseases8 recommended that the biomarker evaluation process should consist of the following three steps: (1) analytical validation, (2) qualification, and (3) use. The need for large numbers of subjects and complex statistical considerations are a challenge when considering experimental designs and when studying panels of biomarkers.9 Additional confounders in the analysis include age, sex, and body mass in the general population10 as well as diurnal variations in biomarkers.11 A basic science understanding with regard to candidate biomarker identification and evaluation is a necessary component to Rehabilomics research design. Because of the frequent coexistence of multiple disorders in individuals seeking care from physiatrists, disease/ dysfunction specificity will need to be established to allow clinical translation of these technologies. Therefore, it is recommended that support be provided in each of these areas to facilitate effective development of rehabilitation-relevant biomarkers. Specifically, the authors recommend that multicenter efforts and multidisciplinary collaborative teams be supported through funding mechanisms that include basic scientists, clinical and translational researchers, bioepidemiology and biostatisticians, as well as clinical care providers. The ability to transition Rehabilomics technology to clinical care also requires the incorporation of rehabilitation and biotechnology collaborators. Variability in response to physical medicine and rehabilitationYbased treatments may be attributable to biologic variation and other unique geneenvironment interactions affecting the individual. Genetic and genomic research is often associated with disease susceptibility; however, the utility of genetic, genomic, transcriptomic, and epigenetic approaches also can help physicians to understand the recovery process after an acquired condition.12 Epigenetic approaches to rehabilitation problems
are particularly attractive because epigenetic changes can introduce environmental exposures into the analysis. Application of genetic-genomic, transcriptomic, and epigenetic approaches to rehabilitation is early in its development, in part because of the need for long-term follow-up of individuals undergoing rehabilitation to fully appreciate the heterogeneity of conditions for which individuals receive physical medicine and rehabilitation treatments. Therefore, support must be provided to build the infrastructural support needed for large-scale, communitybased longitudinal studies that allow for exploration and validation of biologic associations with treatment effects and functional outcomes to be determined. Some initial examples of how Rehabilomics research is contributing to rehabilitation research and care are noted in the traumatic brain injury13Y17 and musculoskeletal arenas.18Y22 These findings all have implications for personalized rehabilitation care and the promotion of quality-care models now mandated in 21st century medical care within the United States. The authors are optimistic that this model will serve as a cornerstone for patientcentered transdisciplinary research involving the wide-ranging populations that require rehabilitation care and that this model can benefit and meet the collective needs of the more than 52 million people with disabilities in the United States that the rehabilitation community serves.
www.ajpmr.com
Rehabilomics Research and Comparative Effectiveness
REFERENCES 1. World Health Organization: International Classification of Functioning, Disability and Health. Geneva, Switzerland, World Health Organization, 2001. Available at: http://www.disabilitaincifre.it/documenti/ICF_ 18.pdf. Accessed April 15, 2014 2. Whyte J, Barrett AM: Advancing the evidence base of rehabilitation treatments: A developmental approach. Arch Phys Med Rehabil 2012;93:S101Y10 3. Patlak M, Levit L: Policy issues in the development of personalized medicine in oncology: Workshop summary (Internet). Rapporteurs: Institute of Medicine. Available at: http://www.nap.edu/catalog/12779.html. Accessed April 14, 2014 4. Wagner AK: TBI translational rehabilitation research in the 21st century: Exploring a Rehabilomics research model. Eur J Phys Rehabil Med 2010;46:549Y56 5. Bruye`re S, VanLooy S, Peterson D: The International Classification of Functioning, Disability and Health (ICF): Contemporary literature overview. Rehabil Psychol 2005;50:113 6. Wagner AK, Zitelli K: A Rehabilomics focused perspective on molecular mechanisms underlying neurological injury, complications, and recovery after severe TBI. Pathophysiology 2013;20:39Y48
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
915
7. Wagner AK: Rehabilomics: a conceptual framework to drive biologics research. PM R 2011;3:28Y30
Associations with post-traumatic seizures after severe TBI. Epilepsy Res 2013;103:180Y94
8. Biomarkers Definitions Working Group: Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69:89Y95
15. Failla MD, Burkhardt JN, Miller MA, et al: Variants of the SLC6A4 gene in depression risk following severe TBI. Brain Inj 2013;27:696Y706
9. Maksymowych WP, Fitzgerald O, Wells GA, et al: Proposal for levels of evidence schema for validation of a soluble biomarker reflecting damage endpoints in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, and recommendations for study design. J Rheumatol 2009;36:1792Y9
17. Wagner AK, Brett CA, McCullough EH, et al: Persistent hypogonadism influences estrogen synthesis, cognition and outcome in males after severe TBI. Brain Inj 2012;26:1226Y42
10. Mouritzen U, Christgau S, Lehmann HJ, et al: Cartilage turnover assessed with a newly developed assay measuring collagen type II degradation products: Influence of age, sex, menopause, hormone replacement therapy, and body mass index. Ann Rheum Dis 2003;62:332Y6
18. Sowa GA, Westrick E, Rajesekhar A, et al: Identification of candidate serum biomarkers for intervertebral disc degeneration in an animal model. PM R 2009;1:536Y40
11. Kong SY, Stabler TV, Criscione LG, et al: Diurnal variation of serum and urine biomarkers in patients with radiographic knee osteoarthritis. Arthritis Rheum 2006;54:2496Y504
19. Sowa GA, Coelho JP, Vo NV, et al: Determination of annulus fibrosus cell response to tensile strain as a function of duration, magnitude and frequency. J Orthop Res 2011;29:1275Y83
12. Conley YP, Alexander S: Genomic, transcriptomic, and epigenomic approaches to recovery after acquired brain injury. PM R 2011;3(6 suppl 1):S52Y8
20. Huang W, Sowa G: Biomarker development for musculoskeletal diseases. PM R 2011;3(6 suppl 1):S39Y44
13. Wagner AK, Miller MA, Scanlon J, et al: Adenosine A1 receptor gene variant associated with posttraumatic seizures after severe TBI. Epilepsy Res 2010;90:259Y72 14. Darrah SD, Miller MA, Ren D, et al: Genetic variability in the glutamic acid decarboxylase gene:
916
16. Hatz LE, Scanlon JM, Niyonkuru C, et al: Association of KIBRA rs17070145 polymorphism and episodic memory in individuals with severe TBI. Brain Inj 2012;26:1658Y69
Wagner and Sowa
21. Sowa GA, Coelho JP, Vo NV, et al: Cells from degenerative intervertebral discs demonstrate unfavorable responses to mechanical and inflammatory stimuli: A pilot study. Am J Phys Med Rehabil 2012;91:846Y55 22. Sowa GA, Coelho JP, Bell KM, et al: Alterations in gene expression in response to compression of nucleus pulposus cells. Spine J 2011;11:36Y43
Am. J. Phys. Med. Rehabil. & Vol. 93, No. 10, October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Management
Affiliations: From the Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pennsylvania.
COMMENTARY
Correspondence: All correspondence and requests for reprints should be addressed to: Amy K. Wagner, MD, University of Pittsburgh, 3471 Fifth Ave, Suite 202 Pittsburgh, PA 15213.
Rehabilomics Research A Model for Translational Rehabilitation and Comparative Effectiveness Rehabilitation Research
Disclosures: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.
0894-9115/14/9310-0913 American Journal of Physical Medicine & Rehabilitation Copyright * 2014 by Lippincott Williams & Wilkins DOI: 10.1097/PHM.0000000000000114
ABSTRACT Wagner AK, Sowa G: Rehabilomics research: a model for translational rehabilitation and comparative effectiveness rehabilitation research. Am J Phys Med Rehabil 2014;93:913Y916. Key Words: Rehabilomics Research, Rehabilitation, Comparative Effectiveness Research, Evidence-Based Medicine, Biomarkers, Personalized Medicine
EXECUTIVE SUMMARY & There exists a particular need for increased personalization in the care of rehabilitation patients because of physical, cognitive, emotional, and social/ environmental heterogeneity. & Rehabilomics research can address this need through examining the full range of individual biologic characteristics that may contribute to heterogeneity, impact recovery, and guide treatment decisions. & It is recommended that additional support be provided to multidisciplinary groups to examine biologic measures contributing to outcome and treatment effects while maintaining the patient-centric focus on function that is unique to rehabilitation care and research. Research in the field of physical medicine and rehabilitation is unique with regard to the broad populations that are served and the wide-ranging individual variability in impairments, functional limitations, and treatment responses. It is well recognized that rehabilitation does not lend itself to a singular Bprotocolized[ plan of care or therapy, and the evaluation of each person must include an individualized assessment of physical, cognitive, emotional, and social systems, each of which uniquely interacts to affect recovery.1 Traditionally, rehabilitation practitioners customize individual rehabilitation protocols for their patients on the basis of the specific needs, supports, and barriers identified, making protocol standardization a challenge. This is particularly problematic when attempting to validate treatment efficacy for specific interventions or clinical decision algorithms. Further, heterogeneity in clinical presentation and treatment response, within the multifaceted aspect of participation, including resumption of personal and societal roles and goals, also creates challenges for rehabilitation researchers to answer pertinent questions regarding rehabilitation treatment optimization and efficacy with traditional study designs.2 However, outcome variability may
www.ajpmr.com
Rehabilomics Research and Comparative Effectiveness Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
913
be attributable to genetic and other biological variation that patients bring to recovery and the unique response to each person’s care and environment. Thus, an individual’s biologic profile could be used to tailor treatments that optimize outcomes. Other fields (e.g., oncology) have embraced this Bomics[based theranostic approach to individualize care on the basis of specific results generated to guide these treatments.3 Beyond the traditional genetic approaches, additional modifiable biologic measures applicable to rehabilitation may help to inform diagnostics, prognostics, as well as treatment approaches and responses. The difficulties with conducting rigorous clinical trials, while preserving the principles of personalized care, can be addressed in many ways by the integration of a Rehabilomics research model. Rehabilomics is a concept developed by the authors’ field of expertise to describe such a personalized approach to rehabilitation research,4 where the full range of individual biologic characteristics is examined to determine which characteristics impact recovery and the nature of this impact. Essentially, this biologically grounded concept provides an B-omic[ overlay to the scientific study of rehabilitation processes and outcomes, personalizing the approach to rehabilitation and aimed at optimizing individual recovery. The World Health Organization’s International Classification of Functioning Disability and Health is central to defining and operationalizing a formula for characterizing function across multiple domains.5 The International Classification of Functioning Disability and Health model specifies common constructs and language for assessing function in clinical care and rehabilitation research that, along with innovative technology linking biorelevant symptoms to both biomarker and outcomes, is central to the Rehabilomics concept. Importantly, pairing biomarkers with a rehabilitation-focused rigorous research design and data collection tools is critical to derive meaningful information about rehabilitation as a health strategy. Therefore, it is recommended that the International Classification of Functioning Disability and Health model be incorporated into future rehabilitationrelevant biomarker identification to ensure relevance to function and patient-centered outcomes. Rehabilomics is a biomarker-focused framework from which to study population-specific mechanisms of recovery,6 and this concept can be used to describe personalized approaches to rehabilitation care and research. A broad range of individual biologic characteristics can be examined, leading to personalized approaches to rehabilitation aimed
914
Wagner and Sowa
at optimizing individual recovery. Rehabilomics can be a helpful tool to bridge the rapidly expanding field of biologics in the context of rehabilitation care. It is recommended that support be provided to facilitate the development of Rehabilomics approaches in various areas of rehabilitation medicine to maximally capitalize on the capacity of biologic outcome measures while maintaining the patientcentric focus on function. As the field of biologics advances and complement traditional approaches, Rehabilomics research programs may emerge as an important tool for successful translation of these agents to clinical care and may allow physical medicine and rehabilitation to be on the cutting edge that shapes this area of biomedical research and care.7 However, more work is needed to identify appropriate markers and understand the sensitivity of these markers to condition progression, recovery, and treatment response to fully incorporate Rehabilomics principles in biologics testing and research design. When developing a portfolio of funding priorities for a contemporary comparative effectiveness research program focused on the area of Rehabilomics, one must consider multiple issues including the following: (1) the definition and operationalization of the term biomarker, which may include genetics, epigenetics, transcriptomics, metabolomics, proteomics, cognitive and/or physical performance metrics, imaging and physiologic measures, as well as interaction with social and environmental exposures, (2) infrastructure needed for large-scale longitudinal studies that are needed to characterize chronic conditions/recovery as well as chronic care interventions, (3) the barriers and opportunities for person-centered care among populations with disabilities, and (4) developing the appropriate research infrastructure and expertise to conduct definitive treatment studies. To achieve these goals, it may be relevant for research programs to leverage National Institutes of Health-funded Clinical and Translational Science Awards (CTSA) site resources for biomarker identification and exploration efforts using state-ofthe-art platforms. In addition, it may be relevant to leverage existing populations, such as what is captured by the National Institute for Disability and Rehabilitation Research (NIDRR) model system databases, for capacity-building initiatives to support larger-scale Rehabilomics investigations. Capacity building through telerehabilitation and point-of-care assay platforms development is needed to support clinical and outcomes data collection to use in combination with rehabilitation-relevant biomarker panels. A biomarker is an objectively measured characteristic that is an indicator of normal biologic
Am. J. Phys. Med. Rehabil. & Vol. 93, No. 10, October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
processes, pathogenic processes, or response to a therapeutic intervention.8 A valuable biomarker should theoretically meet at least 2 criteria: (1) it should be sensitive to the changes of the condition, and (2) it should be specific to a characteristic of the condition. Biomarkers identified in blood and other biofluids are commonly considered in most areas of biomarkers research. However, a range of biomarkers beyond those observed in biofluids can be considered within the context of Rehabilomics research and can include radiographic endpoints, physiologic markers, and even cognitive performance and participations measures. The Institute of Medicine’s Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Diseases8 recommended that the biomarker evaluation process should consist of the following three steps: (1) analytical validation, (2) qualification, and (3) use. The need for large numbers of subjects and complex statistical considerations are a challenge when considering experimental designs and when studying panels of biomarkers.9 Additional confounders in the analysis include age, sex, and body mass in the general population10 as well as diurnal variations in biomarkers.11 A basic science understanding with regard to candidate biomarker identification and evaluation is a necessary component to Rehabilomics research design. Because of the frequent coexistence of multiple disorders in individuals seeking care from physiatrists, disease/ dysfunction specificity will need to be established to allow clinical translation of these technologies. Therefore, it is recommended that support be provided in each of these areas to facilitate effective development of rehabilitation-relevant biomarkers. Specifically, the authors recommend that multicenter efforts and multidisciplinary collaborative teams be supported through funding mechanisms that include basic scientists, clinical and translational researchers, bioepidemiology and biostatisticians, as well as clinical care providers. The ability to transition Rehabilomics technology to clinical care also requires the incorporation of rehabilitation and biotechnology collaborators. Variability in response to physical medicine and rehabilitationYbased treatments may be attributable to biologic variation and other unique geneenvironment interactions affecting the individual. Genetic and genomic research is often associated with disease susceptibility; however, the utility of genetic, genomic, transcriptomic, and epigenetic approaches also can help physicians to understand the recovery process after an acquired condition.12 Epigenetic approaches to rehabilitation problems
are particularly attractive because epigenetic changes can introduce environmental exposures into the analysis. Application of genetic-genomic, transcriptomic, and epigenetic approaches to rehabilitation is early in its development, in part because of the need for long-term follow-up of individuals undergoing rehabilitation to fully appreciate the heterogeneity of conditions for which individuals receive physical medicine and rehabilitation treatments. Therefore, support must be provided to build the infrastructural support needed for large-scale, communitybased longitudinal studies that allow for exploration and validation of biologic associations with treatment effects and functional outcomes to be determined. Some initial examples of how Rehabilomics research is contributing to rehabilitation research and care are noted in the traumatic brain injury13Y17 and musculoskeletal arenas.18Y22 These findings all have implications for personalized rehabilitation care and the promotion of quality-care models now mandated in 21st century medical care within the United States. The authors are optimistic that this model will serve as a cornerstone for patientcentered transdisciplinary research involving the wide-ranging populations that require rehabilitation care and that this model can benefit and meet the collective needs of the more than 52 million people with disabilities in the United States that the rehabilitation community serves.
www.ajpmr.com
Rehabilomics Research and Comparative Effectiveness
REFERENCES 1. World Health Organization: International Classification of Functioning, Disability and Health. Geneva, Switzerland, World Health Organization, 2001. Available at: http://www.disabilitaincifre.it/documenti/ICF_ 18.pdf. Accessed April 15, 2014 2. Whyte J, Barrett AM: Advancing the evidence base of rehabilitation treatments: A developmental approach. Arch Phys Med Rehabil 2012;93:S101Y10 3. Patlak M, Levit L: Policy issues in the development of personalized medicine in oncology: Workshop summary (Internet). Rapporteurs: Institute of Medicine. Available at: http://www.nap.edu/catalog/12779.html. Accessed April 14, 2014 4. Wagner AK: TBI translational rehabilitation research in the 21st century: Exploring a Rehabilomics research model. Eur J Phys Rehabil Med 2010;46:549Y56 5. Bruye`re S, VanLooy S, Peterson D: The International Classification of Functioning, Disability and Health (ICF): Contemporary literature overview. Rehabil Psychol 2005;50:113 6. Wagner AK, Zitelli K: A Rehabilomics focused perspective on molecular mechanisms underlying neurological injury, complications, and recovery after severe TBI. Pathophysiology 2013;20:39Y48
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
915
7. Wagner AK: Rehabilomics: a conceptual framework to drive biologics research. PM R 2011;3:28Y30
Associations with post-traumatic seizures after severe TBI. Epilepsy Res 2013;103:180Y94
8. Biomarkers Definitions Working Group: Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69:89Y95
15. Failla MD, Burkhardt JN, Miller MA, et al: Variants of the SLC6A4 gene in depression risk following severe TBI. Brain Inj 2013;27:696Y706
9. Maksymowych WP, Fitzgerald O, Wells GA, et al: Proposal for levels of evidence schema for validation of a soluble biomarker reflecting damage endpoints in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, and recommendations for study design. J Rheumatol 2009;36:1792Y9
17. Wagner AK, Brett CA, McCullough EH, et al: Persistent hypogonadism influences estrogen synthesis, cognition and outcome in males after severe TBI. Brain Inj 2012;26:1226Y42
10. Mouritzen U, Christgau S, Lehmann HJ, et al: Cartilage turnover assessed with a newly developed assay measuring collagen type II degradation products: Influence of age, sex, menopause, hormone replacement therapy, and body mass index. Ann Rheum Dis 2003;62:332Y6
18. Sowa GA, Westrick E, Rajesekhar A, et al: Identification of candidate serum biomarkers for intervertebral disc degeneration in an animal model. PM R 2009;1:536Y40
11. Kong SY, Stabler TV, Criscione LG, et al: Diurnal variation of serum and urine biomarkers in patients with radiographic knee osteoarthritis. Arthritis Rheum 2006;54:2496Y504
19. Sowa GA, Coelho JP, Vo NV, et al: Determination of annulus fibrosus cell response to tensile strain as a function of duration, magnitude and frequency. J Orthop Res 2011;29:1275Y83
12. Conley YP, Alexander S: Genomic, transcriptomic, and epigenomic approaches to recovery after acquired brain injury. PM R 2011;3(6 suppl 1):S52Y8
20. Huang W, Sowa G: Biomarker development for musculoskeletal diseases. PM R 2011;3(6 suppl 1):S39Y44
13. Wagner AK, Miller MA, Scanlon J, et al: Adenosine A1 receptor gene variant associated with posttraumatic seizures after severe TBI. Epilepsy Res 2010;90:259Y72 14. Darrah SD, Miller MA, Ren D, et al: Genetic variability in the glutamic acid decarboxylase gene:
916
16. Hatz LE, Scanlon JM, Niyonkuru C, et al: Association of KIBRA rs17070145 polymorphism and episodic memory in individuals with severe TBI. Brain Inj 2012;26:1658Y69
Wagner and Sowa
21. Sowa GA, Coelho JP, Vo NV, et al: Cells from degenerative intervertebral discs demonstrate unfavorable responses to mechanical and inflammatory stimuli: A pilot study. Am J Phys Med Rehabil 2012;91:846Y55 22. Sowa GA, Coelho JP, Bell KM, et al: Alterations in gene expression in response to compression of nucleus pulposus cells. Spine J 2011;11:36Y43
Am. J. Phys. Med. Rehabil. & Vol. 93, No. 10, October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
