{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T23:20:24Z","timestamp":1781738424749,"version":"3.54.5"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T00:00:00Z","timestamp":1593388800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T00:00:00Z","timestamp":1593388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"High Value Nutrition National Science Challenge","award":["UOAX1421"],"award-info":[{"award-number":["UOAX1421"]}]},{"name":"The a2 Milk Company Ltd"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Gastroenterol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Adult lactase non-persistence (LNP) is due to low lactase expression, resulting in lactose malabsorption (LM). LNP is a genetic trait, but is typically determined by LM markers including breath H<jats:sub>2<\/jats:sub>, blood glucose, and urinary galactose after a lactose tolerance test. Known validity of these markers using milk is limited, despite being common practice. Compositional variation, such as \u03b2-casein variants, in milk may impact diagnostic efficacy. This study aimed to evaluate the diagnostic accuracy to detect LNP using these commonly measured LM markers after both lactose and milk challenges.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>Fourty healthy young women were challenged with 50\u2009g lactose then randomized for separate cross-over visits to ingest 750\u2009mL milk (37.5\u2009g lactose) as conventional (both A1 and A2 \u03b2-casein) and A1 \u03b2-casein-free (a2 Milk\u2122) milk. Blood, breath and urine were collected prior to and up to 3\u2009h following each challenge. The presence of C\/T<jats:sub>13910<\/jats:sub> and G\/A<jats:sub>22018<\/jats:sub> polymorphisms, determined by restriction fragment length polymorphism, was used as the diagnostic reference for LNP.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Genetic testing identified 14 out of 40 subjects as having LNP (C\/C<jats:sub>13910<\/jats:sub> and G\/G<jats:sub>22018<\/jats:sub>). All three LM markers (breath H<jats:sub>2<\/jats:sub>, plasma glucose and urinary galactose\/creatinine) discriminated between lactase persistence (LP) and LNP following lactose challenge with an area under the receiver operating characteristic (ROC) curve (AUC) of 1.00, 0.75 and 0.73, respectively. Plasma glucose and urinary galactose\/creatinine were unreliable (AUC\u2009&lt;\u20090.70) after milk ingestion. The specificity of breath H<jats:sub>2<\/jats:sub> remained high (100%) when milk was used, but sensitivity was reduced with conventional (92.9%) and a2 Milk\u2122 (78.6%) compared to lactose (sensitivities adjusted for lactose content). The breath H<jats:sub>2<\/jats:sub> optimal cut-off value was lower with a2 Milk\u2122 (13\u2009ppm) than conventional milk (21\u2009ppm). Using existing literature cut-off values the sensitivity and specificity of breath H<jats:sub>2<\/jats:sub> was greater than plasma glucose to detect LNP following lactose challenge whereas values obtained for urinary galactose\/creatinine were lower than the existing literature cut-offs.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>This study showed accurate diagnosis of LNP by breath H<jats:sub>2<\/jats:sub> irrespective of the substrate used, although the diagnostic threshold may vary depending on the lactose substrate or the composition of the milk.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Trial registration<\/jats:title>\n<jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.anzctr.org.au\/Trial\/Registration\/TrialReview.aspx?id=371676\">ACTRN12616001694404<\/jats:ext-link>. Registered prospectively on December 9, 2016.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12876-020-01352-6","type":"journal-article","created":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T13:03:52Z","timestamp":1593435832000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Evaluation of breath, plasma, and urinary markers of lactose malabsorption to diagnose lactase non-persistence following lactose or milk ingestion"],"prefix":"10.1186","volume":"20","author":[{"given":"Aahana","family":"Shrestha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew P. G.","family":"Barnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo K.","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Cameron-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9559-7326","authenticated-orcid":false,"given":"Amber M.","family":"Milan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,29]]},"reference":[{"key":"1352_CR1","first-page":"1","volume":"27","author":"FJ Suchy","year":"2010","unstructured":"Suchy FJ, Brannon PM, Carpenter TO, Fernandez JR, Gilsanz V, Gould JB, et al. NIH consensus development conference statement: lactose intolerance and health. NIH Consens State Sci Statements. 2010;27:1\u201327.","journal-title":"NIH Consens State Sci Statements"},{"key":"1352_CR2","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1016\/S0016-5085(98)70429-9","volume":"114","author":"Y Wang","year":"1998","unstructured":"Wang Y, Harvey CB, Hollox EJ, Phillips AD, Poulter M, Clay P, et al. The genetically programmed down-regulation of lactase in children. Gastroenterology. 1998;114:1230\u20136.","journal-title":"Gastroenterology."},{"key":"1352_CR3","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1093\/qjmed\/hcq082","volume":"103","author":"P Jellema","year":"2010","unstructured":"Jellema P, Schellevis FG, van der Windt D, Kneepkens CMF, van der Horst HE. Lactose malabsorption and intolerance: a systematic review on the diagnostic value of gastrointestinal symptoms and self-reported milk intolerance. Q J Med. 2010;103:555\u201372. https:\/\/doi.org\/10.1093\/qjmed\/hcq082.","journal-title":"Q J Med"},{"key":"1352_CR4","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1111\/apt.13041","volume":"41","author":"MCE Lomer","year":"2015","unstructured":"Lomer MCE. Review article: the aetiology, diagnosis, mechanisms and clinical evidence for food intolerance. Aliment Pharmacol Ther. 2015;41:262\u201375. https:\/\/doi.org\/10.1111\/apt.13041.","journal-title":"Aliment Pharmacol Ther"},{"key":"1352_CR5","doi-asserted-by":"publisher","first-page":"3839","DOI":"10.3390\/nu5103839","volume":"5","author":"C Catassi","year":"2013","unstructured":"Catassi C, Bai JC, Bonaz B, Bouma G, Calabr\u00f2 A, Carroccio A, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013;5:3839\u201353.","journal-title":"Nutrients."},{"key":"1352_CR6","doi-asserted-by":"crossref","unstructured":"Brooke-Taylor S, Dwyer K, Woodford K, Kost N. Systematic Review of the Gastrointestinal Effects of A1 Compared with A2 \u03b2-Casein. Adv Nutr. 2017;2:739\u201348.","DOI":"10.3945\/an.116.013953"},{"key":"1352_CR7","doi-asserted-by":"publisher","first-page":"1634S","DOI":"10.3945\/ajcn.2009.26736O","volume":"89","author":"CM Weaver","year":"2009","unstructured":"Weaver CM. Should dairy be recommended as part of a healthy vegetarian diet? Point Am J Clin Nutr. 2009;89:1634S\u20137S. https:\/\/doi.org\/10.3945\/ajcn.2009.26736O.","journal-title":"Point Am J Clin Nutr"},{"key":"1352_CR8","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/s12937-015-0057-5","volume":"14","author":"EE Quann","year":"2015","unstructured":"Quann EE, Fulgoni VL, Auestad N. Consuming the daily recommended amounts of dairy products would reduce the prevalence of inadequate micronutrient intakes in the United States: diet modeling study based on NHANES 2007\u20132010. Nutr J. 2015;14:90. https:\/\/doi.org\/10.1186\/s12937-015-0057-5.","journal-title":"Nutr J"},{"key":"1352_CR9","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/0003-2697(66)90280-6","volume":"14","author":"M Messer","year":"1966","unstructured":"Messer M, Dahlqvist A. A one-step ultramicro method for the assay of intestinal disaccharidases. Anal Biochem. 1966;14:376\u201392.","journal-title":"Anal Biochem"},{"key":"1352_CR10","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1056\/NEJM197512112932405","volume":"293","author":"AD Newcomer","year":"1975","unstructured":"Newcomer AD, McGill DB, Thomas PJHA. Prospective comparison of indirect methods for detecting lactase deficiency. New Engl J Med. 1975;293:1232\u20136.","journal-title":"New Engl J Med"},{"key":"1352_CR11","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/1471-230X-9-82","volume":"9","author":"\u00d8 Hovde","year":"2009","unstructured":"Hovde \u00d8, Farup PG. A comparison of diagnostic tests for lactose malabsorption--which one is the best? BMC Gastroenterol. 2009;9:82. https:\/\/doi.org\/10.1186\/1471-230X-9-82.","journal-title":"BMC Gastroenterol"},{"key":"1352_CR12","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.clnu.2016.01.006","volume":"36","author":"JL Dom\u00ednguez Jim\u00e9nez","year":"2017","unstructured":"Dom\u00ednguez Jim\u00e9nez JL, Fern\u00e1ndez Su\u00e1rez A, Mu\u00f1oz Colmenero A\u00da, Fatela Cantillo D, L\u00f3pez PI. Primary hypolactasia diagnosis: comparison between the gaxilose test, shortened lactose tolerance test, and clinical parameters corresponding to the C\/T-13910 polymorphism. Clin Nutr. 2017;36:471\u20136. https:\/\/doi.org\/10.1016\/j.clnu.2016.01.006.","journal-title":"Clin Nutr"},{"key":"1352_CR13","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/ng826","volume":"30","author":"NS Enattah","year":"2002","unstructured":"Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, J\u00e4rvel\u00e4 I. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30:233\u20137. https:\/\/doi.org\/10.1038\/ng826.","journal-title":"Nat Genet"},{"key":"1352_CR14","doi-asserted-by":"publisher","first-page":"3508","DOI":"10.3748\/wjg.v13.i25.3508","volume":"13","author":"NS Enattah","year":"2007","unstructured":"Enattah NS, Kuokkanen M, Forsblom C, Natah S, Oksanen A, J\u00e4rvel\u00e4 I, et al. Correlation of intestinal disaccharidase activities with the C\/T-13910 variant and age. World J Gastroenterol. 2007;13:3508\u201312.","journal-title":"World J Gastroenterol"},{"key":"1352_CR15","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s12263-012-0305-7","volume":"8","author":"RAH Kuchay","year":"2013","unstructured":"Kuchay RAH, Anwar M, Thapa BR, Mahmood A, Mahmood S. Correlation of G\/a \u221222018 single-nucleotide polymorphism with lactase activity and its usefulness in improving the diagnosis of adult-type hypolactasia among north Indian children. Genes Nutr. 2013;8:145\u201351.","journal-title":"Genes Nutr"},{"key":"1352_CR16","doi-asserted-by":"publisher","unstructured":"Itan Y, Jones BL, Ingram CJ, Swallow DM, Thomas MG. A worldwide correlation of lactase persistence phenotype and genotypes. BMC Evol Biol. 2010;10. https:\/\/doi.org\/10.1186\/1471-2148-10-36.","DOI":"10.1186\/1471-2148-10-36"},{"key":"1352_CR17","doi-asserted-by":"publisher","first-page":"36","DOI":"10.3109\/00365529409091743","volume":"202","author":"K Villako","year":"1994","unstructured":"Villako K, Maaroos H. Clinical picture of hypolactasia and lactose intolerance. Scand J Gastroenterol Suppl. 1994;202:36\u201354. https:\/\/doi.org\/10.3109\/00365529409091743.","journal-title":"Scand J Gastroenterol Suppl"},{"key":"1352_CR18","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1159\/000084526","volume":"71","author":"V Ojetti","year":"2005","unstructured":"Ojetti V, Nucera G, Migneco A, Gabrielli M, Lauritano C, Danese S, et al. High prevalence of celiac disease in patients with lactose intolerance. Digestion. 2005;71:106\u201310.","journal-title":"Digestion."},{"key":"1352_CR19","first-page":"1148","volume":"92","author":"B Mishkin","year":"1997","unstructured":"Mishkin B, Yalovsky M, Mishkin S. Increased prevalence of lactose malabsorption in Crohn\u2019s disease patients at low risk for lactose malabsorption based on ethnic origin. Am J Gastroenterol. 1997;92:1148\u201353.","journal-title":"Am J Gastroenterol"},{"key":"1352_CR20","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.3390\/nu10111599","volume":"10","author":"F Fassio","year":"2018","unstructured":"Fassio F, Facioni MS, Guagnini F. Lactose Maldigestion, Malabsorption, and intolerance: a comprehensive review with a focus on current management and future perspectives. Nutrients. 2018;10:1599. https:\/\/doi.org\/10.3390\/nu10111599.","journal-title":"Nutrients."},{"key":"1352_CR21","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1056\/NEJM196907172810303","volume":"281","author":"MD Levitt","year":"1969","unstructured":"Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med. 1969;281:122\u20137. https:\/\/doi.org\/10.1056\/NEJM196907172810303.","journal-title":"N Engl J Med"},{"key":"1352_CR22","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1023\/A:1024163327183","volume":"48","author":"F Casellas","year":"2003","unstructured":"Casellas F, Malagelada JR. Applicability of short hydrogen breath test for screening of lactose malabsorption. Dig Dis Sci. 2003;48:1333\u20138.","journal-title":"Dig Dis Sci"},{"key":"1352_CR23","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1111\/jgh.12273","volume":"28","author":"UC Ghoshal","year":"2013","unstructured":"Ghoshal UC, Kumar S, Misra A, Mittal B. Lactose malabsorption diagnosed by 50-g dose is inferior to assess clinical intolerance and to predict response to milk withdrawal than 25-g dose in an endemic area. J Gastroenterol Hepatol. 2013;28:1462\u20138. https:\/\/doi.org\/10.1111\/jgh.12273.","journal-title":"J Gastroenterol Hepatol"},{"key":"1352_CR24","doi-asserted-by":"publisher","DOI":"10.1088\/1752-7155\/10\/1\/016015","volume":"10","author":"V Ruzsanyi","year":"2016","unstructured":"Ruzsanyi V, Heinz-Erian P, Entenmann A, Karall D, M\u00fcller T, Schimkowitsch A, et al. Diagnosing lactose malabsorption in children: difficulties in interpreting hydrogen breath test results. J Breath Res. 2016;10:016015. https:\/\/doi.org\/10.1088\/1752-7155\/10\/1\/016015.","journal-title":"J Breath Res"},{"key":"1352_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1365-2036.2009.03951.x","volume":"29","author":"A Gasbarrini","year":"2009","unstructured":"Gasbarrini A, Corazza GR, Gasbarrini G, Montalto M, Di Stefano MBG. H2-breath testing for carbohydrate malabsorption. Aliment Pharmacol Ther. 2009;29:1\u201349. https:\/\/doi.org\/10.1111\/j.1365-2036.2009.03951.x.","journal-title":"Aliment Pharmacol Ther"},{"key":"1352_CR26","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3109\/00365529309101578","volume":"28","author":"R-JM Brummer","year":"1993","unstructured":"Brummer R-JM, Karibe M. Lactose Malabsorption. Scand J Gastroenterol. 1993;28:65\u20139. https:\/\/doi.org\/10.3109\/00365529309101578.","journal-title":"Scand J Gastroenterol"},{"key":"1352_CR27","unstructured":"Artan R, Bicakci Z, Isitan F. Urinary lactose tolerance test for the detection of lactose malabsorption. Turkish J Gastroenterol. 1998;9:361\u20135."},{"key":"1352_CR28","doi-asserted-by":"crossref","unstructured":"Grant JD, Bezerra JA, Thompson SH. Assessment of Lactose absorption by measurement of urinary galactose. Am Gastroenterol Assoc. 1989;97:895\u20139.","DOI":"10.1016\/0016-5085(89)91494-7"},{"key":"1352_CR29","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1093\/ajcn\/nqy296","volume":"109","author":"N Vionnet","year":"2019","unstructured":"Vionnet N, M\u00fcnger LH, Freiburghaus C, Burton KJ, Pimentel G, Pralong FP, et al. Assessment of lactase activity in humans by measurement of galactitol and galactonate in serum and urine after milk intake. Am J Clin Nutr. 2019;109:470\u20137.","journal-title":"Am J Clin Nutr"},{"key":"1352_CR30","first-page":"103","volume":"33","author":"I Kurt","year":"2003","unstructured":"Kurt I, Abou Ghoush MW, Hasimi A, Serdar MA, Kutluay T. Comparison of indirect methods for lactose malabsorption. Turkish J Med Sci. 2003;33:103\u201310.","journal-title":"Turkish J Med Sci"},{"key":"1352_CR31","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s12937-016-0147-z","volume":"15","author":"S Jianqin","year":"2016","unstructured":"Jianqin S, Leiming X, Lu X, Yelland GW, Ni J, Clarke AJ. Effects of milk containing only A2 beta casein versus milk containing both A1 and A2 beta casein proteins on gastrointestinal physiology, symptoms of discomfort, and cognitive behavior of people with self-reported intolerance to traditional cows\u2019 milk. Nutr J. 2016;15:35. https:\/\/doi.org\/10.1186\/s12937-016-0147-z.","journal-title":"Nutr J"},{"key":"1352_CR32","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1097\/00004836-198706000-00016","volume":"9","author":"FP Villiers","year":"1987","unstructured":"Villiers FP. A standarized milk tolerance test. JClin Gastroenterol. 1987;9:320\u20133.","journal-title":"JClin Gastroenterol"},{"key":"1352_CR33","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1093\/ajcn\/33.3.545","volume":"33","author":"NW Solomons","year":"1980","unstructured":"Solomons NW, Garcia-Ibanez R, Viteri FE. Hydrogen breath test of lactose absorption in adults: the application of physiological doses and whole cow\u2019s milk sources. Am J Clin Nutr. 1980;33:545\u201354.","journal-title":"Am J Clin Nutr"},{"key":"1352_CR34","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1093\/ajcn\/47.1.57","volume":"47","author":"MC Martini","year":"1988","unstructured":"Martini MC, Savaiano DA. Reduced intolerance symptoms from lactose consumed during a meal. Am J Clin Nutr. 1988;47:57\u201360.","journal-title":"Am J Clin Nutr"},{"key":"1352_CR35","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s12937-017-0275-0","volume":"16","author":"M He","year":"2017","unstructured":"He M, Sun J, Jiang ZQ, Yang YX. Effects of cow\u2019s milk beta-casein variants on symptoms of milk intolerance in Chinese adults: a multicentre, randomised controlled study. Nutr J. 2017;16:72. https:\/\/doi.org\/10.1186\/s12937-017-0275-0.","journal-title":"Nutr J"},{"key":"1352_CR36","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1093\/clinchem\/29.3.545","volume":"29","author":"NW Solomons","year":"1983","unstructured":"Solomons NW, Rosado JL. Sensitivity and Specificity of the Hydrogen Breath-Analysis Test for Detecting Malabsorption of Physiological Doses of Lactose. Clin Chem. 1983;29:545\u20138.","journal-title":"Clin Chem"},{"key":"1352_CR37","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.3390\/nu11071636","volume":"11","author":"A Shrestha","year":"2019","unstructured":"Shrestha A, Prodhan UK, Mitchell SM, Sharma P, Barnett MPG, Milan AM, et al. Validity of a portable breath Analyser (AIRE) for the assessment of lactose Malabsorption. Nutrients. 2019;11:1636. https:\/\/doi.org\/10.3390\/nu11071636.","journal-title":"Nutrients."},{"key":"1352_CR38","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1046\/j.1365-2036.2001.00952.x","volume":"15","author":"I Labayen","year":"2001","unstructured":"Labayen I, Forga L, Gonzalez A, Lenoir-Wijnkoop I, Nutr R, Martinez JA. Relationship between lactose digestion, gastrointestinal transit time and symptoms in lactose malabsorbers after dairy consumption. Aliment Pharmacol Ther. 2001;15:543\u20139. https:\/\/doi.org\/10.1046\/j.1365-2036.2001.00952.x.","journal-title":"Aliment Pharmacol Ther"},{"key":"1352_CR39","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.3390\/nu10101492","volume":"10","author":"A Milan","year":"2018","unstructured":"Milan A, Hodgkinson A, Mitchell S, Prodhan U, Prosser C, Carpenter E, et al. Digestive responses to fortified cow or goat dairy drinks: a randomised controlled trial. Nutrients. 2018;10:1492. https:\/\/doi.org\/10.3390\/nu10101492.","journal-title":"Nutrients."},{"key":"1352_CR40","doi-asserted-by":"publisher","first-page":"7285","DOI":"10.3390\/nu7095339","volume":"7","author":"S Pal","year":"2015","unstructured":"Pal S, Woodford K, Kukuljan S, Ho S. Milk Intolerance, Beta-Casein and Lactose. Nutrients. 2015;7:7285\u201397. https:\/\/doi.org\/10.3390\/nu7095339.","journal-title":"Nutrients"},{"key":"1352_CR41","doi-asserted-by":"publisher","unstructured":"Milan AM, Shrestha A, Karlstr\u00f6m HJ, Martinsson JA, Nilsson NJ, Perry JK, et al. Comparison of the impact of bovine milk \u03b2-casein variants on digestive comfort in females self-reporting dairy intolerance: a randomized controlled trial. Am J Clin Nutr. 2019. https:\/\/doi.org\/10.1093\/ajcn\/nqz279.","DOI":"10.1093\/ajcn\/nqz279"},{"key":"1352_CR42","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1007\/s10620-008-0443-3","volume":"54","author":"F Casellas","year":"2009","unstructured":"Casellas F, Varela E, Aparici A, Casaus M, Rodr\u00edguez P. Development, validation, and applicability of a symptoms questionnaire for lactose Malabsorption screening. Dig Dis Sci. 2009;54:1059\u201365.","journal-title":"Dig Dis Sci"},{"key":"1352_CR43","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1136\/bmj.c332","volume":"340","author":"KF Schulz","year":"2010","unstructured":"Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:698\u2013702.","journal-title":"BMJ."},{"key":"1352_CR44","doi-asserted-by":"publisher","unstructured":"Milan AM, Pundir S, Pileggi CA, Markworth JF, Lewandowski PA, Cameron-Smith D. Comparisons of the Postprandial Inflammatory and Endotoxaemic Responses to Mixed Meals in Young and Older Individuals: A Randomised Trial. https:\/\/doi.org\/10.3390\/nu9040354.","DOI":"10.3390\/nu9040354"},{"issue":"Pt 1","key":"1352_CR45","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1258\/acb.2007.007147","volume":"45","author":"JP Waud","year":"2008","unstructured":"Waud JP, Matthews SB, Campbell AK. Measurement of breath hydrogen and methane, together with lactase genotype, defines the current best practice for investigation of lactose sensitivity. Ann Clin Biochem. 2008;45(Pt 1):50\u20138. https:\/\/doi.org\/10.1258\/acb.2007.007147.","journal-title":"Ann Clin Biochem"},{"key":"1352_CR46","first-page":"2013","volume-title":"R: a language and environment for statistical computing","author":"R Core Team","year":"2013","unstructured":"R Core Team. R Core Team. In: R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2013. p. 2013."},{"key":"1352_CR47","volume-title":"Applied Logistic Regression. 2nd edition. United stats of America: A Wiley-Interscience Publication","author":"H DW","year":"2000","unstructured":"DW H, Lemeshow S. Applied Logistic Regression. 2nd edition. United stats of America: A Wiley-Interscience Publication; 2000."},{"key":"1352_CR48","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1136\/pgmj.2004.025551","volume":"81","author":"S Matthews","year":"2005","unstructured":"Matthews S, Waud J, Roberts A, Campbell A. Systemic lactose intolerance: a new perspective on an old problem. Postgrad Med J. 2005;81:167\u201373. https:\/\/doi.org\/10.1136\/pgmj.2004.025551.","journal-title":"Postgrad Med J"},{"key":"1352_CR49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jnci\/djv153","volume":"107","author":"R Simon","year":"2015","unstructured":"Simon R. Specificity, PPV, and NPV for predictive biomarkers. JNCI J Natl Cancer Inst. 2015;107:1\u20139.","journal-title":"JNCI J Natl Cancer Inst"},{"key":"1352_CR50","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1017\/S0007114510001297","volume":"104","author":"D Pohl","year":"2018","unstructured":"Pohl D, Savarino E, Hersberger M, Behlis Z, Stutz B, Goetze O, et al. Excellent agreement between genetic and hydrogen breath tests for lactase deficiency and the role of extended symptom assessment. Br J Nutr. 2018;104:900\u20137. https:\/\/doi.org\/10.1017\/S0007114510001297.","journal-title":"Br J Nutr"},{"key":"1352_CR51","doi-asserted-by":"crossref","unstructured":"Trevethan R. Sensitivity, specificity, and predictive values: foundations, Pliabilities, and pitfalls in research and practice. Front Public Heal. 2017;5:307.","DOI":"10.3389\/fpubh.2017.00307"},{"key":"1352_CR52","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1097\/JTO.0B013E3181EC173D","volume":"5","author":"JN Mandrekar","year":"2010","unstructured":"Mandrekar JN. Receiver operating characteristic curve in diagnostic test assessment. J Thorac Oncol. 2010;5:1315\u20136. https:\/\/doi.org\/10.1097\/JTO.0B013E3181EC173D.","journal-title":"J Thorac Oncol"},{"key":"1352_CR53","doi-asserted-by":"publisher","first-page":"4056","DOI":"10.1039\/C8FO00555A","volume":"9","author":"S Ugidos-Rodr\u00edguez","year":"2018","unstructured":"Ugidos-Rodr\u00edguez S, Matallana-Gonz\u00e1lez MC, S\u00e1nchez-Mata MC. Lactose malabsorption and intolerance: a review. Food Funct. 2018;9:4056\u201368. https:\/\/doi.org\/10.1039\/C8FO00555A.","journal-title":"Food Funct"},{"key":"1352_CR54","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/jes.2008.48","volume":"19","author":"MA Pearson","year":"2009","unstructured":"Pearson MA, Lu C, Schmotzer BJ, Waller LA, Riederer AM. Evaluation of physiological measures for correcting variation in urinary output: implications for assessing environmental chemical exposure in children. J Expo Sci Environ Epidemiol. 2009;19:336\u201342.","journal-title":"J Expo Sci Environ Epidemiol"},{"key":"1352_CR55","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1093\/ajcn\/37.6.941","volume":"37","author":"G Collier","year":"1983","unstructured":"Collier G, O\u2019Dea K. The effect of coingestion of fat on the glucose, insulin, and gastric inhibitory polypeptide responses to carbohydrate and protein. Am J Clin Nutr. 1983;37:941\u20134.","journal-title":"Am J Clin Nutr"},{"key":"1352_CR56","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1093\/ajcn\/26.4.393","volume":"26","author":"J Leichter","year":"1973","unstructured":"Leichter J. Comparison of whole milk and skim milk with aqueous lactose solution in lactose tolerance testing. Am J Clin Nutr. 1973;26:393\u20136.","journal-title":"Am J Clin Nutr"},{"key":"1352_CR57","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0021-9258(18)56577-7","volume":"181","author":"VH Barki","year":"1949","unstructured":"Barki VH, Feigelson P, et al. Factors inflencing galactose utilization. J Biol Chem. 1949;181:565\u201371.","journal-title":"J Biol Chem"},{"key":"1352_CR58","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0021-9258(17)31006-2","volume":"167","author":"L Nieft","year":"1947","unstructured":"Nieft L, Deuel J. The effetc of fat on the absoprtion and utilization of galactose by the rat. J if Biol Chem. 1947;167:521\u20135.","journal-title":"J if Biol Chem"},{"key":"1352_CR59","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1542\/peds.2006-1721","volume":"118","author":"MB Heyman","year":"2006","unstructured":"Heyman MB. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006;118:1279\u201386. https:\/\/doi.org\/10.1542\/peds.2006-1721.","journal-title":"Pediatrics."},{"key":"1352_CR60","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1111\/j.1365-2036.2008.03623.x","volume":"27","author":"L Beyerlein","year":"2008","unstructured":"Beyerlein L, Pohl D, Delco F, Stutz B, Fried M, Tutuian R. Correlation between symptoms developed after the oral ingestion of 50 g lactose and results of hydrogen breath testing for lactose intolerance. Aliment Pharmacol Ther. 2008;27:659\u201365. https:\/\/doi.org\/10.1111\/j.1365-2036.2008.03623.x.","journal-title":"Aliment Pharmacol Ther"},{"key":"1352_CR61","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1136\/bmj.295.6603.876","volume":"295","author":"JM Seakins","year":"1987","unstructured":"Seakins JM, Elliott RB, Quested CM, Matatumua A. Lactose malabsorption in Polynesian and white children in the south West Pacific studied by breath hydrogen technique. BMJ. 1987;295:876\u20138..","journal-title":"BMJ."},{"key":"1352_CR62","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1080\/07315724.1998.10718813","volume":"17","author":"G Carroccio","year":"2013","unstructured":"Carroccio G, Montalto G, Cavera AN. Lactose intolerance and self-reported Milk intolerance: relationship with lactose Maldigestion and nutrient intake clinical and laboratory pearl lactose intolerance and self-reported Milk intolerance: relationship with lactose Maldigestion and nutrient in. J Am Coll Nutr. 2013;17:631\u2013936. https:\/\/doi.org\/10.1080\/07315724.1998.10718813.","journal-title":"J Am Coll Nutr"},{"key":"1352_CR63","doi-asserted-by":"publisher","first-page":"6204","DOI":"10.3748\/wjg.14.6204","volume":"14","author":"F Argnani","year":"2008","unstructured":"Argnani F, Di Camillo M, Marinaro V, Foglietta T, Avallone V, Cannella C, et al. Hydrogen breath test for the diagnosis of lactose intolerance, is the routine sugar load the best one? World J Gastroenterol. 2008;14:6204\u20137.","journal-title":"World J Gastroenterol"},{"key":"1352_CR64","doi-asserted-by":"publisher","first-page":"720","DOI":"10.3109\/09637486.2014.898260","volume":"65","author":"MPG Barnett","year":"2014","unstructured":"Barnett MPG, McNabb WC, Roy NC, Woodford KB, Clarke AJ. Dietary A1 \u03b2 -casein affects gastrointestinal transit time, dipeptidyl peptidase-4 activity, and inflammatory status relative to A2 \u03b2 -casein in Wistar rats. Int J Food Sci Nutr. 2014;65:720\u20137. https:\/\/doi.org\/10.3109\/09637486.2014.898260.","journal-title":"Int J Food Sci Nutr"},{"key":"1352_CR65","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1007\/s00394-013-0606-7","volume":"53","author":"MRU Haq","year":"2014","unstructured":"Haq MRU, Kapila R, Sharma R, Saliganti V, Kapila S. Comparative evaluation of cow \u03b2-casein variants (A1\/A2) consumption on Th2-mediated inflammatory response in mouse gut. Eur J Nutr. 2014;53:1039\u201349. https:\/\/doi.org\/10.1007\/s00394-013-0606-7.","journal-title":"Eur J Nutr"},{"key":"1352_CR66","doi-asserted-by":"publisher","unstructured":"\u00c7AK B. Discussions of Effect A1 and A2 Milk Beta-Casein Gene on Health. Appro Poult Dairy Vet Sci. 2018;3. https:\/\/doi.org\/10.31031\/APDV.2018.03.000556.","DOI":"10.31031\/APDV.2018.03.000556"},{"key":"1352_CR67","doi-asserted-by":"publisher","unstructured":"Behera R, Sahu A, Mandal A, Rai S, Karunakaran M, Dutta T. A1 versus A2 Milk- Impact on Human Health. Int J Livest Res. 2018, 1. https:\/\/doi.org\/10.5455\/ijlr.20170810113426.","DOI":"10.5455\/ijlr.20170810113426"},{"key":"1352_CR68","doi-asserted-by":"publisher","first-page":"168","DOI":"10.3109\/00365520903414176","volume":"45","author":"L Xu","year":"2010","unstructured":"Xu L, Sun H, Zhang X, Wang J, Sun D, Chen F, et al. The-22018A allele matches the lactase persistence phenotype in northern Chinese populations. Scand J Gastroenterol. 2010;45:168\u201374. https:\/\/doi.org\/10.3109\/00365520903414176.","journal-title":"Scand J Gastroenterol"},{"key":"1352_CR69","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1590\/S0100-879X2007001100004","volume":"40","author":"AC Bulh\u00f5es","year":"2007","unstructured":"Bulh\u00f5es AC, Goldani HAS, Oliveira FS, Matte US, Mazzuca RB, Silveira TR. Correlation between lactose absorption and the C\/T-13910 and G\/A-22018 mutations of the lactase-phlorizin hydrolase (LCT) gene in adult-type hypolactasia. Brazilian J Med Biol Res. 2007;40:1441\u20136. https:\/\/doi.org\/10.1590\/S0100-879X2007001100004.","journal-title":"Brazilian J Med Biol Res"},{"key":"1352_CR70","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/J.CLINBIOCHEM.2015.11.001","volume":"49","author":"Z Dzialanski","year":"2016","unstructured":"Dzialanski Z, Barany M, Engfeldt P, Magnuson A, Olsson LA, Nilsson TK. Lactase persistence versus lactose intolerance: is there an intermediate phenotype? Clin Biochem. 2016;49:248\u201352. https:\/\/doi.org\/10.1016\/J.CLINBIOCHEM.2015.11.001.","journal-title":"Clin Biochem"},{"key":"1352_CR71","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1080\/00365520802095485","volume":"43","author":"L Seppo","year":"2008","unstructured":"Seppo L, Tuure T, Korpela R, J\u00e4rvel\u00e4 I, Rasinper\u00e4 H, Sahi T. Can primary hypolactasia manifest itself after the age of 20 years? A two-decade follow-up study. Scand J Gastroenterol. 2008;43:1082\u20137. https:\/\/doi.org\/10.1080\/00365520802095485.","journal-title":"Scand J Gastroenterol"},{"key":"1352_CR72","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1097\/00042737-200503000-00018","volume":"17","author":"C H\u00f6genauer","year":"2005","unstructured":"H\u00f6genauer C, Hammer HF, Mellitzer K, Renner W, Krejs GJ, Toplak H. Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence. Eur J Gastroenterol Hepatol. 2005;17:371\u20136. https:\/\/doi.org\/10.1097\/00042737-200503000-00018.","journal-title":"Eur J Gastroenterol Hepatol"}],"container-title":["BMC Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12876-020-01352-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12876-020-01352-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12876-020-01352-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T23:37:52Z","timestamp":1624923472000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcgastroenterol.biomedcentral.com\/articles\/10.1186\/s12876-020-01352-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,29]]},"references-count":72,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1352"],"URL":"https:\/\/doi.org\/10.1186\/s12876-020-01352-6","relation":{},"ISSN":["1471-230X"],"issn-type":[{"value":"1471-230X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,29]]},"assertion":[{"value":"11 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was conducted according to the Declaration of Helsinki and approved by the New Zealand Health and Disability Ethics Committees (Reference no.16\/STH\/175). All participants provided written informed consent.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"AS, MPGB, JKP and AMM have no conflicts to declare. DCS was employed by a2MC from 12 October 2018 to 31 January 2019. This was after the study described here, and all associated analyses reported within this manuscript, had been completed.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"204"}}