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Background Clinical research with adolescents can be challenging due to issues of informed consent, parental involvement, institutional review board requirements, and adolescent psychosocial development. This presents a dilemma, particularly in the area of sexual health research, as adolescents are disproportionately affected by sexually transmitted infections such as human papillomavirus (HPV). To successfully conduct adolescent research in the clinical setting, one requires an awareness of state statutes regarding adolescent confidentiality and consent for medical care, and a close partnership with the IRB. Case Study In 2007, the Mount Sinai Adolescent Health Center (MSAHC) in collaboration with the Albert Einstein College of Medicine developed a longitudinal research study to examine the natural history of oral, cervical, and anal HPV in an adolescent female population engaged in high-risk sexual behaviors. We use this research project as a case study to explore the ethical, methodological, and clinical issues related to conducting adolescent health research. Summary and Conclusions Several strategies were identified to promote adolescent study participation, including: (1) building a research team that is motivated to work with adolescents; (2) combining research and patient care visits to avoid duplication of services; and (3) establishing a personalized communication network with participants. Using these methods, adolescent sexual health research can successfully be integrated into the clinical setting. While retaining a prospective cohort of adolescents has its challenges, a persistent and multi-disciplinary approach can help improve recruitment, sustain participation, and acquire critical data that will lead to improved healthcare knowledge applicable to understudied populations of adolescents.

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