DO IT Trial: vitamin D Outcomes and Interventions in Toddlers - a TARGet Kids! randomized controlled trial

Jonathon L Maguire, Catherine S Birken, Mark B Loeb, Muhammad Mamdani, Kevin Thorpe, Jeffrey S Hoch, Tony Mazzulli, Cornelia M Borkhoff, Colin Macarthur, Patricia C Parkin, TARGet Kids! Collaboration, Jonathon L Maguire, Catherine S Birken, Mark B Loeb, Muhammad Mamdani, Kevin Thorpe, Jeffrey S Hoch, Tony Mazzulli, Cornelia M Borkhoff, Colin Macarthur, Patricia C Parkin, TARGet Kids! Collaboration

Abstract

Background: Vitamin D levels are alarmingly low (<75 nmol/L) in 65-70% of North American children older than 1 year. An increased risk of viral upper respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of 'high dose' (2000 IU/day) vs. 'standard dose' (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of 'high dose' vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI.

Methods/design: This study is a pragmatic randomized controlled trial. Over 4 successive winters we will recruit 750 healthy children 1-5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be randomized to the 'standard dose' or 'high dose' oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups.

Discussion: Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs. This information will assist in determining practice and health policy recommendations related to vitamin D supplementation in healthy Canadian preschoolers.

Figures

Figure 1
Figure 1
DO IT! Trial Schematic.

References

    1. Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest. 2006;116:2062–72. doi: 10.1172/JCI29449.
    1. CIHI. National Ambulatory Care Reporting System. Ottawa: Canadian Institute for Health Information; 2005.
    1. Maguire JL, Birken CS, O’Connor DL, Macarthur C, Thorpe KE, Mamdani M, Parkin PC. Prevalence and predictors of low vitamin D in urban Canadian toddlers. Pediatr Child Health. 2011;16:e11–e15.
    1. Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122:1142–52. doi: 10.1542/peds.2008-1862.
    1. CPS. Vitamin D supplementation: Recommmendations for Canadian mothers and infants. Paediatr Child Health. 2007;12:589–93.
    1. Greer FR. 25-Hydroxyvitamin D: functional outcomes in infants and young children. Am J Clin Nutr. 2008;88:529S–533S.
    1. Greer FR. Defining vitamin D deficiency in children: beyond 25-OH vitamin D serum concentrations. Pediatrics. 2009;124:1471–3. doi: 10.1542/peds.2009-2307.
    1. Litonjua AA. Childhood asthma may be a consequence of vitamin D deficiency. Curr Opin Allergy Clin Immunol. 2009;9:202–7. doi: 10.1097/ACI.0b013e32832b36cd.
    1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–81. doi: 10.1056/NEJMra070553.
    1. Bouillon R. In: Endocrinology. DeGroot LJ, Jameson JL, editor. Philadelphia: W.B. Saunders; 2001. Vitamin D: From photosynthesis, metabolism, and action to clinical applications; pp. 1009–28.
    1. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80(Suppl):1689S–1696S.
    1. MacLaughlin JA, Anderson RR, Holick MF. Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin. Science. 1982;216:1001–3. doi: 10.1126/science.6281884.
    1. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988;67:373–8. doi: 10.1210/jcem-67-2-373.
    1. Behrman RK, Jenson HB R. Nelson Textbook of Pediatrics. 16. Philadelphia: W.B. Saunders Company; 2000.
    1. Roth DE, Martz P, Yeo R, Prosser C, Bell M, Jones AB. Are national vitamin D guidelines sufficient to maintain adequate blood levels in children? Can J Public Health. 2005;96:443–9.
    1. Health Canada. Do Canadian children meet their nutrient requirements through food intake alone? 2007. . 2007, Cat. H164-112.
    1. Gordon CM, Feldman HA, Sinclair L, Williams AL, Kleinman PK, Perez-Rossello J, Cox JE. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med. 2008;162:505–12. doi: 10.1001/archpedi.162.6.505.
    1. Mansbach JM, Ginde AA, Camargo CA Jr. Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D? Pediatrics. 2009;124:1404–10. doi: 10.1542/peds.2008-2041.
    1. Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML. Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001–2004. Pediatrics. 2009;124:e362–70. doi: 10.1542/peds.2009-0051.
    1. Stoian CA, Lyon M, Cox RG, Stephure DK, Mah JK. Vitamin D concentrations among healthy children in Calgary, Alberta. Paediatr Child Health. 2011;16:82–6.
    1. Hammer LD, Bryson S, Agras WS. Development of feeding practices during the first 5 years of life. Arch Pediatr Adolesc Med. 1999;153:189–94.
    1. CPS. Nutrition for Health Term Infants - Statement of the joint working group. Canada: Canadian Paediatric Society, Dieticians of Canada and Health Canada; 2009.
    1. Northstone K, Rogers I, Emmett P. Drinks consumed by 18-month-old children: are current recommendations being followed? Eur J Clin Nutr. 2002;56:236–44. doi: 10.1038/sj.ejcn.1601313.
    1. Korsch M, Nelson K, Reinhart J. Guidelines for Health Supervision III. Vol 50. American Academy of Pediatrics: Elk Grove Village, Ill; 1997. Feeding behaviors in infancy and early childhood; p. 57.
    1. Baker RD, Greer FR. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age) Pediatrics. 2010;126:1040–50. doi: 10.1542/peds.2010-2576.
    1. Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 2006;92:4–8. doi: 10.1016/j.pbiomolbio.2006.02.016.
    1. Langlois K, Greene-Finestone L, Little J, Hidiroglou N, Whitting S. Vitamin D status of Canadians as measured in the 2007 to 2009 Canadian Health Measures Survey. Health Reports (Statistics Canada) 2010;21:47–55.
    1. Maguire JL, Birken C, Mamdani M, Thorpe KE, Parkin PC. How much cow’s milk should preschoolers be drinking?: A TARGet Kids! study. Proceedings of the Pediatric Academic Societies Annual Meeting. 2011. pp. E-PAS–1385.5.
    1. Maguire JL, Birken C, Mamdani M, Thorpe KE, Parkin PC. Milk volume, vitamin D supplementation, outdoor activity and season are important predictors of vitamin D serum level in preschoolers: A TARGet Kids! study. Proceedings of the Pediatric Academic Societies Annual Meeting. 2011. pp. E-PAS–2155.8.
    1. Gessner BD, Plotnik J, Muth PT. 25-hydroxyvitamin D levels among healthy children in Alaska. J Pediatr. 2003;143:434–7. doi: 10.1067/S0022-3476(03)00410-4.
    1. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med. 2004;158:531–7. doi: 10.1001/archpedi.158.6.531.
    1. Newhook LA, Sloka S, Grant M, Randell E, Kovacs CS, Twells LK. Vitamin D insufficiency common in newborns, children and pregnant women living in Newfoundland and Labrador. Canada. Matern Child Nut. 2009;5:186–91. doi: 10.1111/j.1740-8709.2008.00157.x.
    1. Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency rickets among children in Canada. CMAJ. 2007;177:161–6. doi: 10.1503/cmaj.061377.
    1. Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, Lemeur H. Vitamin D supplementation in pregnancy: a controlled trial of two methods. Obstet Gynecol. 1986;68:300–4. doi: 10.1097/00006250-198609000-00002.
    1. Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C. Princess Anne Hospital Study Group. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet. 2006;367:36–43. doi: 10.1016/S0140-6736(06)67922-1.
    1. Markestad T, Aksnes L, Ulstein M, Aarskog D. 25-Hydroxyvitamin D and 1,25-dihydroxyvitamin D of D2 and D3 origin in maternal and umbilical cord serum after vitamin D2 supplementation in human pregnancy. Am J Clin Nutr. 1984;40:1057–63.
    1. Lee JM, Smith JR, Philipp BL, Chen TC, Mathieu J, Holick MF. Vitamin D deficiency in a healthy group of mothers and newborn infants. Clin Pediatr (Phila) 2007;46:42–4. doi: 10.1177/0009922806289311.
    1. Hollis BW, Pittard WB 3rd. Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J Clin Endocrinol Metab. 1984;59:652–7. doi: 10.1210/jcem-59-4-652.
    1. Bianchi ML. Osteoporosis in children and adolescents. Bone. 2007;41:486–95. doi: 10.1016/j.bone.2007.07.008.
    1. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358:1500–3. doi: 10.1016/S0140-6736(01)06580-1.
    1. Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child. 2008;93:512–7. doi: 10.1136/adc.2007.128579.
    1. Heikkinen T, Jarvinen A. The common cold. Lancet. 2003;361:51–9. doi: 10.1016/S0140-6736(03)12162-9.
    1. Burt CW, McCaig LF, Rechtsteiner EA. Ambulatory medical care utilization estimates for. Adv Data. 2005;2007:1–15.
    1. Lambert SB, Allen KM, Druce JD, Birch CJ, Mackay IM, Carlin JB, Carapetis JR, Sloots TP, Nissen MD, Nolan TM. Community epidemiology of human metapneumovirus, human coronavirus NL63, and other respiratory viruses in healthy preschool-aged children using parent-collected specimens. Pediatrics. 2007;120:e929–37. doi: 10.1542/peds.2006-3703.
    1. Lambert SB, Allen KM, Carter RC, Nolan TM. The cost of community-managed viral respiratory illnesses in a cohort of healthy preschool-aged children. Respir Res. 2008;9:11. doi: 10.1186/1465-9921-9-11.
    1. Collet JP, Burtin P, Kramer MS, Floret D, Bossard N, Ducruet T. Type of day-care setting and risk of repeated infections. Pediatrics. 1994;94:997–9.
    1. Schwartz B, Giebink GS, Henderson FW, Reichler MR, Jereb J, Collet JP. Respiratory infections in day care. Pediatrics. 1994;94:1018–20.
    1. Benediktsdottir B. Upper airway infections in preschool children-frequency and risk factors. Scand J Prim Health Care. 1993;11:197–201. doi: 10.3109/02813439308994830.
    1. Kvaerner KJ, Nafstad P, Jaakkola JJ. Upper respiratory morbidity in preschool children: a cross-sectional study. Arch Otolaryngol Head Neck Surg. 2000;126:1201–6. doi: 10.1001/archotol.126.10.1201.
    1. Chonmaitree T, Revai K, Grady JJ, Clos A, Patel JA, Nair S, Fan J, Henrickson KJ. Viral upper respiratory tract infection and otitis media complication in young children. Clin Infect Dis. 2008;46:815–23. doi: 10.1086/528685.
    1. Carabin H, Gyorkos TW, Soto JC, Penrod J, Joseph L, Collet JP. Estimation of direct and indirect costs because of common infections in toddlers attending day care centers. Pediatrics. 1999;103:556–64. doi: 10.1542/peds.103.3.556.
    1. Haskins R. Acute illness in day care: how much does it cost? Bull N Y Acad Med. 1989;65:319–43.
    1. Hope-Simpson RE. The Transmission of Epidemic Influenza. New York: Plenum Press; 1992.
    1. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129–40. doi: 10.1017/S0950268806007175.
    1. Herr C, Shaykhiev R, Bals R. The role of cathelicidin and defensins in pulmonary inflammatory diseases. Expert Opin Biol Ther. 2007;7:1449–61. doi: 10.1517/14712598.7.9.1449.
    1. Bartley J. Vitamin D, innate immunity and upper respiratory tract infection. J Laryngol Otol. 2010;124:465–9.
    1. Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW. Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol. 2008;181:7090–9.
    1. Diamond G, Legarda D, Ryan LK. The innate immune response of the respiratory epithelium. Immunol Rev. 2000;173:27–38. doi: 10.1034/j.1600-065X.2000.917304.x.
    1. Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005;3:238–50. doi: 10.1038/nrmicro1098.
    1. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–3. doi: 10.1126/science.1123933.
    1. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005;19:1067–77. doi: 10.1096/fj.04-3284com.
    1. Aloia JF, Talwar SA, Pollack S, Yeh J. A randomized controlled trial of vitamin D3 supplementation in African American women. Arch Intern Med. 2005;165:1618–23. doi: 10.1001/archinte.165.14.1618.
    1. Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009;169:384–90. doi: 10.1001/archinternmed.2008.560.
    1. Laaksi I, Ruohola JP, Tuohimaa P, Auvinen A, Haataja R, Pihlajamaki H, Ylikomi T. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. Am J Clin Nutr. 2007;86:714–7.
    1. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5:e11088. doi: 10.1371/journal.pone.0011088.
    1. Camargo CA Jr, Ingham T, Wickens K. Cord blood 25-hydroxyvitamin D levels and risk of childhood wheeze in New Zealand [abstract] Am J Respir Crit Care Med. 2008;177(Suppl):A993.
    1. Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, Berbari N. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect. 2009;137:1396–1404. doi: 10.1017/S0950268809002404.
    1. Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pihlajamaki H. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis. 2010;202:809–14. doi: 10.1086/654881.
    1. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91:1255–60. doi: 10.3945/ajcn.2009.29094.
    1. HealthCanada. Vitamin D. Recommendations and review status. 2010. . Accessed January 5, 2010.
    1. To T, Gershon A, Tassoudji M. ICES Investigative Report: The Burden of Asthma in Ontario. Toronto: Institute for Clinical Evaluative Sciences; 2006.
    1. CIHI. Respiratory disease in Canada. Ottawa: Canadian Institute for Health Information: Canadian Lung Association, Statistics Canada; 2001.
    1. ICES. Research Atlas: Inpatient and day surgery use by children in Ontario. Toronto: Institute for Clinical Evaluative Sciences; 1998.
    1. Krahn MD, Berka C, Langlois P, Detsky AS. Direct and indirect costs of asthma in Canada, 1990. CMAJ. 1996;154:821–31.
    1. Litonjua AA, Weiss ST. Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol. 2007;120:1031–5. doi: 10.1016/j.jaci.2007.08.028.
    1. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469–78. doi: 10.1111/j.1398-9995.2004.00526.x.
    1. Bosse Y, Maghni K, Hudson TJ. 1alpha,25-dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes. Physiol Genomics. 2007;29:161–8.
    1. Song Y, Qi H, Wu C. Effect of 1,25-(OH)2D3 (a vitamin D analogue) on passively sensitized human airway smooth muscle cells. Respirology. 2007;12:486–94. doi: 10.1111/j.1440-1843.2007.01099.x.
    1. Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, Weiss ST. Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med. 2004;170:1057–65. doi: 10.1164/rccm.200404-447OC.
    1. Saadi A, Gao G, Li H, Wei C, Gong Y, Liu Q. Association study between vitamin D receptor gene polymorphisms and asthma in the Chinese Han population: a case–control study. BMC Med Genet. 2009;10:71.
    1. Bosse Y, Lemire M, Poon AH, Daley D, He JQ, Sandford A, White JH, James AL, Musk AW, Palmer LJ, Raby BA, Weiss ST, Kozyrskyj AL, Becker A, Hudson TJ, Laprise C. Asthma and genes encoding components of the vitamin D pathway. Respir Res. 2009;10:98. doi: 10.1186/1465-9921-10-98.
    1. Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest. 2005;128:3792–8. doi: 10.1378/chest.128.6.3792.
    1. Brehm JM, Schuemann B, Fuhlbrigge AL, Hollis BW, Strunk RC, Zeiger RS, Weiss ST, Litonjua AA. Childhood Asthma Management Program Research Group. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol. 2010;126:52–8 e55. doi: 10.1016/j.jaci.2010.03.043.
    1. Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DY. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol. 2010;125:995–1000. doi: 10.1016/j.jaci.2010.03.008.
    1. Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM, Forno E, Laskey D, Sylvia JS, Hollis BW, Weiss ST, Litonjua AA. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med. 2009;179:765–71. doi: 10.1164/rccm.200808-1361OC.
    1. StatsCan. Canadian Community Health Survey. 2010. Available online: Accessed January 5, 2010.
    1. Thorpe KE, Zwarenstein M, Oxman AD, Treweek S, Furberg CD, Altman DG, Tunis S, Bergel E, Harvey I, Magid DJ, Chalkidou K. A pragmatic–explanatory continuum indicator summary (PRECIS): a tool to help trial designers. CMAJ. 2009;180:E47–E57. doi: 10.1503/cmaj.090523. This article was published simultaneously in the May 2009 issue of the J Clin Epidemiol .
    1. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR, Krleža-Jeric K, Laupacis A, Moher D. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. doi: 10.1136/bmj.e7586.
    1. Chan AW, Tetzlaff J, Altman DG, Gøtzsche PC, Horobjartsson A. The Spirit Initiative: Defining Standard Protocol Items for Randomized Trials. Enhancing the Quality and Transparency of Health Research. 2010. . Accessed September 6, 2010.
    1. Schulz KF, Altman DG, Moher D. CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. doi: 10.1136/bmj.c332.
    1. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998;8:222–30. doi: 10.1007/s001980050058.
    1. Aloia JF, Talwar SA, Pollack S, Feuerman M, Yeh JK. Optimal vitamin D status and serum parathyroid hormone concentrations in African American women. Am J Clin Nutr. 2006;84:602–9.
    1. PHAC. Respiratory virus surveillance. 2010. . Accessed August 22, 2010.
    1. Haynes RB, Dantes R. Patient compliance and the conduct and interpretation of therapeutic trials. Control Clin Trials. 1987;8:12–9. doi: 10.1016/0197-2456(87)90021-3.
    1. Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP. Does this patient have influenza? JAMA. 2005;293:987–97. doi: 10.1001/jama.293.8.987.
    1. King JC Jr, Stoddard JJ, Gaglani MJ, Moore KA, Magder L, McClure E, Rubin JD, Englund JA, Neuzik K. Effectiveness of school-based influenza vaccination. N Engl J Med. 2006;355:2523–32. doi: 10.1056/NEJMoa055414.
    1. Esposito S, Molteni CG, Daleno C, Valzano A, Tagliabue C, Galeone C, Milani G, Fossali E, Marchisio P, Principi N. Collection by trained pediatricians or parents of mid-turbinate nasal flocked swabs for the detection of influenza viruses in childhood. Virol J. 2010;7:85. doi: 10.1186/1743-422X-7-85.
    1. Lambert SB, Allen KM, Nolan TM. Parent-collected respiratory specimens-a novel method for respiratory virus and vaccine efficacy research. Vaccine. 2008;26:1826–31. doi: 10.1016/j.vaccine.2008.01.055.
    1. Templeton KE, Scheltinga SA, Beersma MF, Kroes AC, Claas EC. Rapid and sensitive method using multiplex real-time PCR for diagnosis of infections by influenza a and influenza B viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4. J Clin Microbiol. 2004;42:1564–9. doi: 10.1128/JCM.42.4.1564-1569.2004.
    1. Mahony J, Chong S. Clinical evaluation of a new ID-Tag RVP assay for the detection of 20 respiratory viruses. Clin Microbiol Infect. 2007;1732:224.
    1. Jacobs B, Young NL, Dick PT, Ipp MM, Dutkowski R, Davies HD, Langley JM, Greenberg S, Stephens D, Wang EE. Canadian Acute Respiratory Illness and Flu Scale (CARIFS): development of a valid measure for childhood respiratory infections. J Clin Epidemiol. 2000;53:793–9. doi: 10.1016/S0895-4356(99)00238-3.
    1. Belshe RB, Mendelman PM, Treanor J, King J, Gruber WC, Piedra P, Bernstein DI, Hayden FG, Kotloff K, Zangwill K, Iacuzio D, Wolff M. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med. 1998;338:1405–12. doi: 10.1056/NEJM199805143382002.
    1. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, Mitchell EA, Pearce N, Sibbald B, Stewart AW. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J Mar. 1995;8:483–91. doi: 10.1183/09031936.95.08030483.
    1. Singh RJ, Taylor RL, Reddy GS, Grebe SK. C-3 epimers can account for a significant proportion of total circulating 25-hydroxyvitamin D in infants, complicating accurate measurement and interpretation of vitamin D status. J Clin Endocrinol Metab. 2006;91:3055–61. doi: 10.1210/jc.2006-0710.
    1. DiaSorin. The Diagnostic Specialist. 2010. Accessed September 6, 2010.
    1. Carter GD, Carter R, Jones J, Berry J. How accurate are assays for 25-hydroxyvitamin D? Data from the international vitamin D external quality assessment scheme. Clin Chem. 2004;50:2195–7. doi: 10.1373/clinchem.2004.040683.
    1. Morinis J, Maguire J, Khovratovich M, McCrindle BW, Parkin PC, Birken CS. Paediatric obesity research in early childhood and the primary care setting: The TARGet Kids! research network. Int J Environ Res Public Health. 2012;9:1343–54. doi: 10.3390/ijerph9041343.
    1. Gozdzik A, Barta JL, Weir A, Cole DE, Vieth R, Whiting SJ, Parra EJ. Serum 25-hydroxyvitamin D concentrations fluctuate seasonally in young adults of diverse ancestry living in Toronto. J Nutr. 2010;140:2213–20. doi: 10.3945/jn.110.126284.
    1. Shriver MD, Parra EJ. Comparison of narrow-band reflectance spectroscopy and tristimulus colorimetry for measurements of skin and hair color in persons of different biological ancestry. Am J Phys Anthropol. 2000;112:17–27. doi: 10.1002/(SICI)1096-8644(200005)112:1<17::AID-AJPA3>;2-D.
    1. Clarys P, Alewaeters K, Lambrecht R, Barel AO. Skin color measurements: comparison between three instruments: the Chromameter(R), the DermaSpectrometer(R) and the Mexameter(R) Skin Res Technol. 2000;6:230–8. doi: 10.1034/j.1600-0846.2000.006004230.x.
    1. Hunter S, Wells KJ, Jacobsen PB. Assessment of elementary school students’ sun protection behaviors. Pediatr Dermatol. 2010;27:182–8. doi: 10.1111/j.1525-1470.2009.00940.x.
    1. Maguire JL, Birken CS, Jacobson S, Peer M, Taylor C, Kambalia A, Mekky M, Thorpe K, Parkin PC. Office-based intervention to reduce bottle use among toddlers: TARGet Kids! pragmatic, randomized trial. Pediatrics. 2010;126:e343–50. doi: 10.1542/peds.2009-3583.
    1. Fisher LD, Dixon DO, Herson J, Frankowski RK, Hearron MS, Peace KE. Statistical issues in drug research and development. New York: Marcel Dekker; 1990. Intention to treat in clinical trials.
    1. Andersen PK, Gill RD. Cox’s regression model for counting processes: A large sample study. Ann Statist. 1982;10:1100–20. doi: 10.1214/aos/1176345976.
    1. Fendrick AM, Monto AS, Nightengale B, Sarnes M. The economic burden of non-influenza-related viral respiratory tract infection in the United States. Arch Intern Med. 2003;163:487–94. doi: 10.1001/archinte.163.4.487.
    1. Hoch JS. Improving efficiency and value in palliative care with net benefit regression: an introduction to a simple method for cost-effectiveness analysis with person-level data. J Pain Symptom Manage. 2009;38:54–61. doi: 10.1016/j.jpainsymman.2009.04.010.
    1. Hoch JS, Briggs AH, Willan AR. Something old, something new, something borrowed, something blue: a framework for the marriage of health econometrics and cost-effectiveness analysis. Health Econ. 2002;11:415–30. doi: 10.1002/hec.678.
    1. Gordon CM, Williams AL, Feldman HA, May J, Sinclair L, Vasquez A, Cox JE. Treatment of hypovitaminosis D in infants and toddlers. J Clin Endocrinol Metab. 2008;93:2716–21. doi: 10.1210/jc.2007-2790.
    1. Tau C, Ciriani V, Scaiola E, Acuna M. Twice single doses of 100,000 IU of vitamin D in winter is adequate and safe for prevention of vitamin D deficiency in healthy children from Ushuaia, Tierra Del Fuego, Argentina. J Steroid Biochem Mol Biol. 2007;103:651–4. doi: 10.1016/j.jsbmb.2006.12.027.
    1. Vieth R. Vitamin D toxicity, policy, and science. J Bone Miner Res. 2007;22(Suppl 2):V64–8.
    1. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842–56.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi