Rakhi P. Naik, MD, MHS; Kim Smith-Whitley, MD; Kathryn L. Hassell, MD; Nkeiruka I. Umeh, BA; Mariane de Montalembert, MD, PhD; Puneet Sahota, MD, PhD; Carlton Haywood Jr., PhD; Jean Jenkins, PhD, RN; Michele A. Lloyd-Puryear, MD, PhD; Clinton H. Joiner, MD, PhD; Vence L. Bonham, JD *; Gregory J. Kato, MD *
Acknowledgment: The authors thank Nedra Whitehead, PhD, and Meera Viswanathan, PhD (RTI International), for initial systematic collection of the literature and development of the quality assessment protocol for this study; Vonna Drayton, PhD, and Chanza Baytop, MPH, DrPH (formerly of Abt Associates), for assistance in training National Human Genome Research Institute (NHGRI) staff to conduct full-text review, data abstraction, and review of literature with the authorship team; Allan Porowski, MPA (Abt Associates), and Chanza Baytop, MPH, DrPH, for help in developing the strength-of-evidence assessment tool tailored for this review and working with the authorship team to establish a consistent review of the studies; Verma Walker, MLS, Brigit Sullivan, MLS, and Dera Tompkins, MLS (National Institutes of Health Library), for their comprehensive search of the databases to identify articles for this study; David Kanney, MBA (Computational and Statistical Genomics Branch, NHGRI), for development of the database for use by the authorship team to review all articles and report assessments; and Khadijah Abdallah, MPH, Dana Franklin, MPH, Colleen Clark, BS, Jamal Jefferson, BS, MBA, and Anitra Persaud, BA (Social and Behavioral Research Branch, NHGRI), for data retrieval and support of the authorship team.
Grant Support: In part by grant ZIAHG200394 from the Division of Intramural Research at NHGRI (Mr. Bonham) and grant K08HL125100 from the National Heart, Lung, and Blood Institute (Dr. Naik).
Disclosures: Dr. Naik reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr. de Montalembert reports grants and personal fees from Novartis and grants and personal fees from Addmedica outside the submitted work. Dr. Joiner reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study and personal fees from Global Blood Therapeutics outside the submitted work. Dr. Kato reports consulting for several pharmaceutical companies and receiving research funding from one, all targeted at treatments for sickle cell disease; there is no actual conflict of interest with the present manuscript on sickle cell trait, which is not involved in any treatment development by any company. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-1161.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Proctor & Gamble, Pfizer, and Johnson & Johnson.
Reproducible Research Statement:Study protocol and statistical code: Not available. Data set: Available from Mr. Bonham (e-mail, firstname.lastname@example.org).
Corresponding Author: Vence L. Bonham, JD, National Human Genome Research Institute, 31 Center Drive, Bethesda, MD 20892; e-mail, email@example.com.
Current Author Addresses: Dr. Naik: Johns Hopkins University, 1830 East Monument Street, Suite 7300, Baltimore, MD 21205.
Dr. Smith-Whitley: The Children's Hospital of Philadelphia, 11th Floor Colket Building, 3401 Civic Center Boulevard, Philadelphia, PA 19104.
Dr. Hassell: University of Colorado, 13121 East 17th Avenue, C-222 Education 2 South, Room 3211, Aurora, CO 80045.
Ms. Umeh and Dr. Jenkins: National Human Genome Research Institute, 31 Center Drive, Room B1B37G, Bethesda, MD 20892.
Dr. de Montalembert: Hôpital Necker–Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France.
Dr. Sahota: University of Pennsylvania, 3535 Market Street, 2nd Floor, Philadelphia, PA 19104.
Dr. Haywood: Johns Hopkins University, 2024 East Monument Street, Suite 2-600, Baltimore, MD 21205.
Dr. Lloyd-Puryear: 7101 Wisconsin Avenue #1101, Bethesda, MD 20814.
Dr. Joiner: Emory University, 1405 Clifton Road, Atlanta, GA 30322.
Mr. Bonham: National Human Genome Research Institute, 31 Center Drive, Bethesda, MD 20892.
Dr. Kato: University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261.
Author Contributions: Conception and design: R.P. Naik, K. Smith-Whitley, K.L. Hassell, M.A. Lloyd-Puryear, V.L. Bonham, G.J. Kato.
Analysis and interpretation of the data: R.P. Naik, K. Smith-Whitley, K.L. Hassell, N.I. Umeh, C. Haywood, J. Jenkins, M.A. Lloyd-Puryear, C.H. Joiner, V.L. Bonham, G.J. Kato.
Drafting of the article: R.P. Naik, K.L. Hassell, P. Sahota, C. Haywood, J. Jenkins, M.A. Lloyd-Puryear, V.L. Bonham, G.J. Kato.
Critical revision of the article for important intellectual content: R.P. Naik, K. Smith-Whitley, K.L. Hassell, M.A. Lloyd-Puryear, C.H. Joiner, V.L. Bonham, G.J. Kato.
Final approval of the article: R.P. Naik, K. Smith-Whitley, K.L. Hassell, N.I. Umeh, M. de Montalembert, P. Sahota, C. Haywood, J. Jenkins, M.A. Lloyd-Puryear, C.H. Joiner, V.L. Bonham, G.J. Kato.
Provision of study materials or patients: V.L. Bonham.
Statistical expertise: R.P. Naik, C. Haywood, V.L. Bonham.
Obtaining of funding: V.L. Bonham.
Administrative, technical, or logistic support: N.I. Umeh, V.L. Bonham.
Collection and assembly of data: R.P. Naik, K.L. Hassell, N.I. Umeh, M. de Montalembert, P. Sahota, J. Jenkins, C.H. Joiner, V.L. Bonham.
Although sickle cell trait (SCT) is largely a benign carrier state, it may increase risk for certain clinical outcomes.
To evaluate associations between SCT and clinical outcomes in children and adults.
English-language searches of PubMed, CINAHL, the Cochrane Library, Current Contents Connect, Scopus, and Embase (1 January 1970 to 30 June 2018) and bibliographies of review articles.
Observational controlled studies (published in English) in children or adults that examined an association between SCT and any of 24 clinical outcomes specified a priori in the following 6 categories: exertion-related injury; renal, vascular, pediatric, and surgery- or trauma-related outcomes; and overall mortality.
A single reviewer extracted study data, which was checked by another; 2 reviewers independently assessed study quality; and strength of evidence was assessed by consensus.
Of 7083 screened studies, 41 met inclusion criteria. High-strength evidence supported a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. Moderate-strength evidence supported a positive association between SCT and exertional rhabdomyolysis and a null association between SCT and deep venous thrombosis, heart failure or cardiomyopathy, stroke, and pediatric height or weight. Absolute risks for thromboembolism and rhabdomyolysis were small. For the remaining 15 clinical outcomes, data were insufficient or strength of evidence was low.
Publication bias was possible, and high-quality evidence was scant.
Sickle cell trait is a risk factor for a few adverse health outcomes, such as pulmonary embolism, kidney disease, and exertional rhabdomyolysis, but does not seem to be associated with such complications as heart failure and stroke. Insufficient data or low-strength evidence exists for most speculated complications of SCT.
National Human Genome Research Institute.
Naik RP, Smith-Whitley K, Hassell KL, Umeh NI, de Montalembert M, Sahota P, et al. Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review. Ann Intern Med. [Epub ahead of print 30 October 2018]169:619–627. doi: 10.7326/M18-1161
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Published: Ann Intern Med. 2018;169(9):619-627.
Published at www.annals.org on 30 October 2018
Hematology/Oncology, Red Cell Disorders.
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