Appendix - List of Relevant studies included and excluded ...cambridge.org:id:... · Web viewClancy R, Ren Z, Turton J, Pang G, Wettstein A. Molecular evidence for mycobacterium

Epidemiology and Infection

The Zoonotic Potential of Mycobacterium avium ssp. paratuberculosis: Systematic review and

meta-analyses of the evidence.

L. A. Waddell *, A. Rajić, K. Stärk, and S. McEwen

Supplementary Material

ContentsAppendix - List of Relevant studies included and excluded from the SR-MA on the zoonotic potential of M. paratuberculosis.....................................................................................................................................2

Appendix- Meta-analysis Forest Plots and Meta-Regression results presented in the tables 1-4 of the zoonotic potential of M. paratuberculosis – SR-MA..................................................................................19

Systematic Review Update Protocol..........................................................................................................26

Summary of risk of bias and study level GRADE components by study-outcome for included in the zoonotic potential of M. paratuberculosis SR-MA.....................................................................................39

Supplementary Material – Zoonotic potential of MAP SR-MA 1

Appendix - List of Relevant studies included and excluded from the SR-MA on the zoonotic potential of M. paratuberculosis.List of Included Studies:

Case control

Year – SR Reference ID – (reference number)

1. 1999 13356 SV (1)

2. 2011 20 (2)

3. 2011 30 (3)

4. 2011 40 (4)

5. 2011 70 (5)

6. 2011 150 (6)

7. 2011 170 (7)

8. 2011 190 (8)

9. 2011 220 (9)

10. 2010 280 (10)

11. 2010 320 (11)

12. 2010 510 (12)

13. 2010 520 (13)

14. 2010 550 (14)

15. 2009 610 (15)

16. 2009 800 (16)

17. 2009 860 (17)

18. 2009 910 (18)

19. 2008 1210 (19)

20. 2008 1230 (20)

21. 2008 1260 (21)

22. 2008 1300 (22)

23. 2009 10176 SV (23)

24. 2006 10557 SV (24)

25. 2006 12828 SV (25)


26. 2011 10007 (26)

27. 2013 10017 (27)

28. 2013 10019 (28)

29. 2013 10029 (29)

30. 2012 10053 (30)

31. 2010 10082 (31)

32. 2013 10086 (32)

33. 2011 10113 (33)

34. 2011 10114 (34)

35. 1994 12-2005 (35)

36. 2004 141-2005 (36)

37. 1992 14-2005 (37)

38. 2004 162-2005 (38)

39. 2003 172-2005 (39)

40. 2002 205-2005 (40)

41. 1999 2255-2005 (41)

42. 2000 234-2005 (42)

43. 1988 2417-2005 (43)

44. 1999 25-2005 (44)

45. 2001 272-2005 (45)

46. 2001 279-2005 (46)

47. 1980 28-2005 (47)

48. 2000 282-2005 (48)

49. 2005 2862-2005 (49)

50. 2000 288-2005 (50)

51. 2005 2945-2005 (51)

52. 1995 314-2005 (52)

53. 1999 329-2005 (53)

54. 1999 332-2005 (54)

55. 2002 353-2005 (55)

56. 1998 363-2005 (56)

57. 1998 373-2005 (57)


58. 1997 397-2005 (58)

59. 1996 408-2005 (59)

60. 1996 414-2005 (60)

61. 1996 418-2005 (61)

62. 1996 428-2005 (62)

63. 1995 430-2005 (63)

64. 1995 435-2005 (64)

65. 1995 441-2005 (65)

66. 1995 44-2005 (66)

67. 2004 450-2005 (67)

68. 1994 461-2005 (68)

69. 1994 474-2005 (69)

70. 1994 477-2005 (70)

71. 1993 495-2005 (71)

72. 1993 508-2005 (72)

73. 1992 523-2005 (73)

74. 1992 524-2005 (74)

75. 1991 539-2005 (75)

76. 1991 544-2005 (76)

77. 2005 55-2005 (77)

78. 1988 581-2005 (78)

79. 1988 585-2005 (79)

80. 1987 593-2005 (80)

81. 1987 595-2005 (81)

82. 2003 6-2005 (82)

83. 1998 630-2005 (83)

84. 1998 654-2005 (84)

85. 2003 67-2005 (85)

86. 2000 40-2005 (86)

87. 1998 89-2005 (87)

88. 1992 519-2005 (88)

89. 1996 10944 SV (89)


90. 2002 10831 SV (90)

91. 2012 10003 (91)

92. 2013 10006 (92)

93. 2009 10245 SV (93)

94. 2008 10348 SV (94)

95. 2002 10814 (95)

96. 1993 11014 SV (96)

97. 1991 2786-2005 (97)

98. 2006 153-2005 (98)

99. 1992 11-2005 (99)

100. 2007 61-2008 (100)

101. 2006 236-2008 (101)

102. 2005 259-2008 (102)

103. 2007 58-2008 (103)

104. 2006 66-2008 (104)

105. 2007 35-2008 (105)

106. 2006 64-2008 (106)

107. 2005 122-2008 (107)

108. 10002-2013 (108)

109. 10003-2013 (109)

110. 10006-2013 (110)

111. 10007-2013 (111)

112. 10005-2013 (112)

113. 10001-2013 (113)

114. 10000-2013 (114)

115. 10008-2013 (115)

116. 541-2005 (116)

Prevalence

117. 2009 3030 (117)118. 2010 2650 (118)119. 2011 210 (119)120. 2006 2969-2005 (120)


121. 2010 410 (121)

Challenge Trials

122. 1989 559-2005 (122)

123. 1986 2495-2005 (123)

Molecular Epidemiology Studies

124. 2011 10128 (124)

125. 2000 301-2005 (125)

126. 2004 98- 2005 (126)

127. 2003 190- 2005 (127)

128. 1997 402- 2005 (128)

Excluded at full paper level:

Case controls.

1. 1993 11029 SV (129) Ex sarcoidosis

2. 2000 274-2005 (130)

3. 1986 601-2005 (131)

4. 2000 699-2005 (132)

5. 1991 789-2005 (133)

6. 1984 266-2005 (134)

7. 2004 398-2005 (135)

8. 2011 10095 (136)

9. 2013 10030 (137)

10. 1997 393-2005 (138)

11. 2008 1180 (139)

12. 2007 25-2008 (140)

Prevalence:

13. 2008 1360 (141)

14. 2010 1560 (142)


15. 2008 8560 (143)

16. 2006 179-2008 (144)

References

1. Naser SA, Felix J, Liping H, Romero C, Naser N, Walsh A, Safranek W. Occurrence of the IS900 gene in mycobacterium avium complex derived from HIV patients. [Internet]. 1999;13(5):367-72. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-0032848865&partnerID=40&md5=5b62204e3c0f8b063e20e662983eeb1b

2. Di Sabatino A, Paccagnini D, Vidali F, Rosu V, Biancheri P, Cossu A, Zanetti S, Corazza GR, Sechi LA. Detection of mycobacterium avium subsp. paratuberculosis (MAP)-specific IS900 DNA and antibodies against MAP peptides and lysate in the blood of crohn's disease patients. Inflamm Bowel Dis [Internet]. 2010 09/02

3. Tuci A, Tonon F, Castellani L, Sartini A, Roda G, Marocchi M, Caponi A, Munarini A, Rosati G, Ugolini G, Fuccio L, Scagliarini M, Bazzoli F, Belluzzi A. Fecal detection of mycobacterium avium paratuberculosis using the IS900 DNA sequence in crohn's disease and ulcerative colitis patients and healthy subjects. [Internet]. 2011;56(10):2957-62. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-80054729018&partnerID=40&md5=b4ea329e449454c602d3d478f1410ab6

4. Rath T, Roderfeld M, Bl+¦cher S, Rhode A, Basler T, Akineden +, Abdulmawjood A, Halwe JM, Goethe R, B++lte M, Roeb E. Presence of intestinal mycobacterium avium subspecies paratuberculosis (MAP) DNA is not associated with altered MMP expression in ulcerative colitis. [Internet]. 2011;11 Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-79953756685&partnerID=40&md5=d9f055738b297a6a374230251f206fc4

5. Imirzalioglu C, Dahmen H, Hain T, Billion A, Kuenne C, Chakraborty T, Domann E. Highly specific and quick detection of mycobacterium avium subsp. paratuberculosis in feces and gut tissue of cattle and humans by multiple real-time PCR assays. J Clin Microbiol [Internet]. 2011 May;49(5):1843-52.

6. Lee A, Griffiths TA, Parab RS, King RK, Dubinsky MC, Urbanski SJ, Wrobel I, Rioux KP. Association of mycobacterium avium subspecies paratuberculosis with crohn disease in pediatric patients. J Pediatr Gastroenterol Nutr [Internet]. 2011 02;52(2):170-4.

7. Campos N, Magro F, Castro AR, Cabral J, Rodrigues P, Silva R, Appelberg R, Rodrigues S, Lopes S, Macedo G, Sarmento A. Macrophages from IBD patients exhibit defective tumour necrosis factor-alpha secretion but otherwise normal or augmented pro-inflammatory responses to infection. Immunobiology [Internet]. 2011 01/12

8. Biet F, Gendt L, Anton E, Ballot E, Hugot JP, Johanet C. Serum antibodies to mycobacterium avium subspecies paratuberculosis combined with anti-saccharomyces cerevisiae antibodies in crohn's disease patients: Prevalence and diagnostic role. Dig Dis Sci [Internet]. 2011 01/08

9. Bach H, Ko HH, Raizman EA, Attarian R, Cho B, Biet F, Enns R, Bressler B. Immunogenicity of mycobacterium avium subsp. paratuberculosis proteins in crohn's disease patients. Scand J Gastroenterol [Internet]. 2011 01;46(1):30-9.


http://www.scopus.com/inward/record.url?eid=2-s2.0-79953756685&partnerID=40&md5=d9f055738b297a6a374230251f206fc4

http://www.scopus.com/inward/record.url?eid=2-s2.0-79953756685&partnerID=40&md5=d9f055738b297a6a374230251f206fc4

http://www.scopus.com/inward/record.url?eid=2-s2.0-80054729018&partnerID=40&md5=b4ea329e449454c602d3d478f1410ab6

http://www.scopus.com/inward/record.url?eid=2-s2.0-80054729018&partnerID=40&md5=b4ea329e449454c602d3d478f1410ab6

http://www.scopus.com/inward/record.url?eid=2-s2.0-0032848865&partnerID=40&md5=5b62204e3c0f8b063e20e662983eeb1b

http://www.scopus.com/inward/record.url?eid=2-s2.0-0032848865&partnerID=40&md5=5b62204e3c0f8b063e20e662983eeb1b

10. Ricanek P, Lothe SM, Szpinda I, Jorde AT, Brackmann S, Perminow G, Jorgensen KK, Rydning A, Vatn MH, Tonjum T. Paucity of mycobacteria in mucosal bowel biopsies from adults and children with early inflammatory bowel disease. J Crohns Colitis [Internet]. 2010 11;4(5):561-6.

11. Mendoza JL, San-Pedro A, Culebras E, Cies R, Taxonera C, Lana R, Urcelay E, de la Torre F, Picazo JJ, Diaz-Rubio M. High prevalence of viable mycobacterium avium subspecies paratuberculosis in crohn's disease. World J Gastroenterol [Internet]. 2010 09/28;16(36):4558-63.

12. Shin AR, Kim HJ, Cho SN, Collins MT, Manning EJ, Naser SA, Shin SJ. Identification of seroreactive proteins in the culture filtrate antigen of mycobacterium avium ssp. paratuberculosis human isolates to sera from crohn's disease patients. FEMS Immunol Med Microbiol [Internet]. 2010 02;58(1):128-37.

13. Sibartie S, Scully P, Keohane J, O'Neill S, O'Mahony J, O'Hanlon D, Kirwan WO, O'Mahony L, Shanahan F. Mycobacterium avium subsp. paratuberculosis (MAP) as a modifying factor in crohn's disease. Inflamm Bowel Dis [Internet]. 2010 02;16(2):296-304.

14. Sasikala M, Reddy DN, Pratap N, Sharma SK, Balkumar PR, Sekaran A, Banerjee R, Reddy DB. Absence of mycobacterium avium ss paratuberculosis-specific IS900 sequence in intestinal biopsy tissues of indian patients with crohn's disease. Indian J Gastroenterol [Internet]. 2009 10/31;28(5):169-74.

15. Kirkwood CD, Wagner J, Boniface K, Vaughan J, Michalski WP, Catto-Smith AG, Cameron DJ, Bishop RF. Mycobacterium avium subspecies paratuberculosis in children with early-onset crohn's disease. Inflamm Bowel Dis [Internet]. 2009 11;15(11):1643-55.

16. Olsen I, Tollefsen S, Aagaard C, Reitan LJ, Bannantine JP, Andersen P, Sollid LM, Lundin KE. Isolation of mycobacterium avium subspecies paratuberculosis reactive CD4 T cells from intestinal biopsies of crohn's disease patients. PLoS One [Internet]. 2009;4(5):e5641.

17. Parrish NM, Radcliff RP, Brey BJ, Anderson JL, Clark DLJ, Koziczkowski JJ, Ko CG, Goldberg ND, Brinker DA, Carlson RA, Dick JD, Ellingson JL. Absence of mycobacterium avium subsp. paratuberculosis in crohn's patients. Inflamm Bowel Dis [Internet]. 2009 04;15(4):558-65.

18. Juste RA, Elguezabal N, Pavon A, Garrido JM, Geijo M, Sevilla I, Cabriada JL, Tejada A, Garcia-Campos F, Casado R, Ochotorena I, Izeta A. Association between mycobacterium avium subsp. paratuberculosis DNA in blood and cellular and humoral immune response in inflammatory bowel disease patients and controls. Int J Infect Dis [Internet]. 2009 03;13(2):247-54.

19. Bentley RW, Keenan JI, Gearry RB, Kennedy MA, Barclay ML, Roberts RL. Incidence of mycobacterium avium subspecies paratuberculosis in a population-based cohort of patients with crohn's disease and control subjects. Am J Gastroenterol [Internet]. 2008 05;103(5):1168-72.

20. Chamberlin W, Naser SA. Blood cultures of 19 crohn's disease patients. Am J Gastroenterol [Internet]. 2008 03;103(3):802-3.

21. Singh AV, Singh SV, Makharia GK, Singh PK, Sohal JS. Presence and characterization of mycobacterium avium subspecies paratuberculosis from clinical and suspected cases of crohn's disease and in the healthy human population in india. Int J Infect Dis [Internet]. 2008 03;12(2):190-7.

22. Ren Z, Turton J, Borody T, Pang G, Clancy R. Selective Th2 pattern of cytokine secretion in mycobacterium avium subsp. paratuberculosis infected crohn's disease. J Gastroenterol Hepatol [Internet]. 2008 02;23(2):310-4.


23. Paccagnini D, Sieswerda L, Rosu V, Masala S, Pacifico A, Gazouli M, Ikonomopoulos J, Ahmed N, Zanetti S, Sechi LA. Linking chronic infection and autoimmune diseases: Mycobacterium avium subspecies paratuberculosis, SLC11A1 polymorphisms and type-1 diabetes mellitus. PLoS One [Internet]. 2009;4(9):e7109.

24. Polymeros D, Bogdanos DP, Day R, Arioli D, Vergani D, Forbes A. Does cross-reactivity between mycobacterium avium paratuberculosis and human intestinal antigens characterize crohn's disease? Gastroenterology [Internet]. 2006 07;131(1):85-96.

25. Netea MG, van der Meer, J. W., Ferwerda G, Kullberg BJ. Defective acute inflammation in crohn's disease. [Internet]. 2006;368(9535):577-8. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-33746913910&partnerID=40&md5=23dacd30f2457c6c0c031a3a015284ab

26. Cossu A, Rosu V, Paccagnini D, Cossu D, Pacifico A, Sechi LA. MAP3738c and MptD are specific tags of mycobacterium avium subsp. paratuberculosis infection in type I diabetes mellitus. [Internet]. 2011;141(1):49-57.

27. Magin WS, Van Kruiningen HJ, Colombel JF. Immunohistochemical search for viral and bacterial antigens in crohn's disease. [Internet]. 2013;7(2):161-6.

28. Molicotti P, Scanu AM, Lumbau A, Cannas S, Bua A, Luglie P, Zanetti S. Molecular identification of mycobacterium avium subspecies paratuberculosis in oral biopsies of crohn's disease patients. [Internet]. 2013;5(1):18, 4749,5-18.

29. Verdier J, Deroche L, Allez M, Loy C, Biet F, Bodier CC, Bay S, Ganneau C, Matysiak-Budnik T, Reyrat JM, Heyman M, Cerf-Bensussan N, Ruemmele FM, Menard S. Specific IgG response against mycobacterium avium paratuberculosis in children and adults with crohn's disease. [Internet]. 2013;8(5):e62780.

30. Elguezabal N, Chamorro S, Molina E, Garrido JM, Izeta A, Rodrigo L, Juste RA. Lactase persistence, NOD2 status and mycobacterium avium subsp. paratuberculosis infection associations to inflammatory bowel disease. [Internet]. 2012;4(1):6, 4749,4-6.

31. Masala S, Cossu D, Pacifico A, Molicotti P, Sechi LA. Sardinian type 1 diabetes patients, transthyretin and mycobacterium avium subspecies paratuberculosis infection. [Internet]. 2012;4(1):24, 4749,4-24.

32. Naser SA, Thanigachalam S, Dow CT, Collins MT. Exploring the role of mycobacterium avium subspecies paratuberculosis in the pathogenesis of type 1 diabetes mellitus: A pilot study. [Internet]. 2013;5(1) Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-84878815827&partnerID=40&md5=7c1255e4e1a76ce4a7fdb7500c58de45

33. Singh AV, Singh SV, Singh PK, Sohal JS, Singh MK. High prevalence of mycobacterium avium subspecies paratuberculosis ('indian bison type') in animal attendants suffering from gastrointestinal complaints who work with goat herds endemic for johne's disease in india. [Internet]. 2011;15(10):e677-83.

34. Singh AV, Singh SV, Verma DK, Yadav R, Singh PK, Sohal JS. Evaluation of "indigenous absorbed ELISA kit" for the estimation of seroprevalence of mycobacterium avium subspecies paratuberculosis antibodies in human beings in north india. [Internet]. 2011;2011:636038.


http://www.scopus.com/inward/record.url?eid=2-s2.0-84878815827&partnerID=40&md5=7c1255e4e1a76ce4a7fdb7500c58de45

http://www.scopus.com/inward/record.url?eid=2-s2.0-84878815827&partnerID=40&md5=7c1255e4e1a76ce4a7fdb7500c58de45

http://www.scopus.com/inward/record.url?eid=2-s2.0-33746913910&partnerID=40&md5=23dacd30f2457c6c0c031a3a015284ab

http://www.scopus.com/inward/record.url?eid=2-s2.0-33746913910&partnerID=40&md5=23dacd30f2457c6c0c031a3a015284ab

35. Dell'Isola B, Poyart C, Goulet O, Mougenot JF, Sadoun-Journo E, Brousse N, Schmitz J, Ricour C, Berche P. Detection of mycobacterium paratuberculosis by polymerase chain reaction in children with crohn's disease. J Infect Dis [Internet]. 1994 02;169(2):449-51.

36. Naser SA, Ghobrial G, Romero C, Valentine JF. Culture of mycobacterium avium subspecies paratuberculosis from the blood of patients with crohn's disease. Lancet [Internet]. 2004 09/18;364(9439):1039-44.

37. Elsaghier A, Prantera C, Moreno C, Ivanyi J. Antibodies to mycobacterium paratuberculosis-specific protein antigens in crohn's disease. Clin Exp Immunol [Internet]. 1992 12;90(3):503-8.

38. Sechi LA, Mura M, Tanda E, Lissia A, Fadda G, Zanetti S. Mycobacterium avium sub. paratuberculosis in tissue samples of crohn's disease patients. New Microbiol [Internet]. 2004 01;27(1):75-7.

39. Bernstein CN, Nayar G, Hamel A, Blanchard JF. Study of animal-borne infections in the mucosas of patients with inflammatory bowel disease and population-based controls. J Clin Microbiol [Internet]. 2003 11;41(11):4986-90.

40. Ryan P, Bennett MW, Aarons S, Lee G, Collins JK, O'Sullivan GC, O'Connell J, Shanahan F. PCR detection of mycobacterium paratuberculosis in crohn's disease granulomas isolated by laser capture microdissection. Gut [Internet]. 2002 11;51(5):665-70.

41. Cohavy O, Harth G, Horwitz M, Eggena M, Landers C, Sutton C, Targan SR, Braun J. Identification of a novel mycobacterial histone H1 homologue (HupB) as an antigenic target of pANCA monoclonal antibody and serum immunoglobulin A from patients with crohn's disease. Infect Immun [Internet]. 1999 12;67(12):6510-7.

42. Collins MT, Lisby G, Moser C, Chicks D, Christensen S, Reichelderfer M, Hoiby N, Harms BA, Thomsen OO, Skibsted U, Binder V. Results of multiple diagnostic tests for mycobacterium avium subsp. paratuberculosis in patients with inflammatory bowel disease and in controls. J Clin Microbiol [Internet]. 2000 12;38(12):4373-81.

43. Kobayashi K, Brown WR, Brennan PJ, Blaser MJ. Serum antibodies to mycobacterial antigens in active crohn's disease. Gastroenterology [Internet]. 1988 06;94(6):1404-11.

44. Kanazawa K, Haga Y, Funakoshi O, Nakajima H, Munakata A, Yoshida Y. Absence of mycobacterium paratuberculosis DNA in intestinal tissues from crohn's disease by nested polymerase chain reaction. J Gastroenterol [Internet]. 1999 04;34(2):200-6.

45. Hulten K, El-Zimaity HM, Karttunen TJ, Almashhrawi A, Schwartz MR, Graham DY, El-Zaatari FA. Detection of mycobacterium avium subspecies paratuberculosis in crohn's diseased tissues by in situ hybridization. Am J Gastroenterol [Internet]. 2001 05;96(5):1529-35.

46. Olsen I, Wiker HG, Johnson E, Langeggen H, Reitan LJ. Elevated antibody responses in patients with crohn's disease against a 14-kDa secreted protein purified from mycobacterium avium subsp. paratuberculosis. Scand J Immunol [Internet]. 2001 02;53(2):198-203.

47. Matthews N, Mayberry JF, Rhodes J, Neale L, Munro J, Wensinck F, Lawson GH, Rowland AC, Berkhoff GA, Barthold SW. Agglutinins to bacteria in crohn's disease. Gut [Internet]. 1980 05;21(5):376-80.


48. Gibson J, Riggio M, McCreary C, Lennon A, Toner M. Looking for mycobacterium paratuberculosis DNA by polymerase chain reaction (PCR) in orofacial granulomatosis (OFG) and oral crohn's disease tissue in an irish population. Ir Med J [Internet]. 2000 10;93(7):218.

49. Autschbach F, Eisold S, Hinz U, Zinser S, Linnebacher M, Giese T, Loffler T, Buchler MW, Schmidt J. High prevalence of mycobacterium avium subspecies paratuberculosis IS900 DNA in gut tissues from individuals with crohn's disease. Gut [Internet]. 2005 07;54(7):944-9.

50. Naser SA, Hulten K, Shafran I, Graham DY, El-Zaatari FA. Specific seroreactivity of crohn's disease patients against p35 and p36 antigens of M. avium subsp. paratuberculosis. Vet Microbiol [Internet]. 2000 12/20;77(3-4):497-504.

51. Sechi LA, Scanu AM, Molicotti P, Cannas S, Mura M, Dettori G, Fadda G, Zanetti S. Detection and isolation of mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without crohn's disease in sardinia. Am J Gastroenterol [Internet]. 2005 07;100(7):1529-36.

52. Murray A, Oliaro J, Schlup MM, Chadwick VS. Mycobacterium paratuberculosis and inflammatory bowel disease: Frequency distribution in serial colonoscopic biopsies using the polymerase chain reaction. Microbios [Internet]. 1995;83(337):217-28.

53. El-Zaatari FA, Naser SA, Hulten K, Burch P, Graham DY. Characterization of mycobacterium paratuberculosis p36 antigen and its seroreactivities in crohn's disease. Curr Microbiol [Internet]. 1999 08;39(2):115-9.

54. Suenaga K, Yokoyama Y, Nishimori I, Sano S, Morita M, Okazaki K, Onishi S. Serum antibodies to mycobacterium paratuberculosis in patients with crohn's disease. Dig Dis Sci [Internet]. 1999 06;44(6):1202-7.

55. Fujita H, Eishi Y, Ishige I, Saitoh K, Takizawa T, Arima T, Koike M. Quantitative analysis of bacterial DNA from mycobacteria spp., bacteroides vulgatus, and escherichia coli in tissue samples from patients with inflammatory bowel diseases. J Gastroenterol [Internet]. 2002;37(7):509-16.

56. Kallinowski F, Wassmer A, Hofmann MA, Harmsen D, Heesemann J, Karch H, Herfarth C, Buhr HJ. Prevalence of enteropathogenic bacteria in surgically treated chronic inflammatory bowel disease. Hepatogastroenterology [Internet]. 1998 10/31;45(23):1552-8.

57. Chiba M, Fukushima T, Horie Y, Iizuka M, Masamune O. No mycobacterium paratuberculosis detected in intestinal tissue, including peyer's patches and lymph follicles, of crohn's disease. J Gastroenterol [Internet]. 1998 08;33(4):482-7.

58. Al-Shamali M, Khan I, Al-Nakib B, Al-Hassan F, Mustafa AS. A multiplex polymerase chain reaction assay for the detection of mycobacterium paratuberculosis DNA in crohn's disease tissue. Scand J Gastroenterol [Internet]. 1997 08;32(8):819-23.

59. Mishina D, Katsel P, Brown ST, Gilberts EC, Greenstein RJ. On the etiology of crohn disease. Proc Natl Acad Sci U S A [Internet]. 1996 09/03;93(18):9816-20.

60. Walmsley RS, Ibbotson JP, Chahal H, Allan RN. Antibodies against mycobacterium paratuberculosis in crohn's disease. QJM [Internet]. 1996 03;89(3):217-21.


61. Dumonceau JM, Van Gossum A, Adler M, Fonteyne PA, Van Vooren JP, Deviere J, Portaels F. No mycobacterium paratuberculosis found in crohn's disease using polymerase chain reaction. Dig Dis Sci [Internet]. 1996 02;41(2):421-6.

62. Frank TS, Cook SM. Analysis of paraffin sections of crohn's disease for mycobacterium paratuberculosis using polymerase chain reaction. Mod Pathol [Internet]. 1996 01;9(1):32-5.

63. Kreuzpaintner G, Kirschner P, Wallner A, Kolble R, Hesterberg R, Thomas L, Borchard F. Mycobacteria of runyon groups I, II and IV do not play an aetiological role in crohn's disease. Eur J Gastroenterol Hepatol [Internet]. 1995 12;7(12):1177-82.

64. Rowbotham DS, Howdle PD, Trejdosiewicz LK. Peripheral cell-mediated immune response to mycobacterial antigens in inflammatory bowel disease. Clin Exp Immunol [Internet]. 1995 12;102(3):456-61.

65. Rowbotham DS, Mapstone NP, Trejdosiewicz LK, Howdle PD, Quirke P. Mycobacterium paratuberculosis DNA not detected in crohn's disease tissue by fluorescent polymerase chain reaction. Gut [Internet]. 1995 11;37(5):660-7.

66. Suenaga K, Yokoyama Y, Okazaki K, Yamamoto Y. Mycobacteria in the intestine of japanese patients with inflammatory bowel disease. Am J Gastroenterol [Internet]. 1995 01;90(1):76-80.

67. Bernstein CN, Blanchard JF, Rawsthorne P, Collins MT. Population-based case control study of seroprevalence of mycobacterium paratuberculosis in patients with crohn's disease and ulcerative colitis. J Clin Microbiol [Internet]. 2004 03;42(3):1129-35.

68. Lisby G, Andersen J, Engbaek K, Binder V. Mycobacterium paratuberculosis in intestinal tissue from patients with crohn's disease demonstrated by a nested primer polymerase chain reaction. Scand J Gastroenterol [Internet]. 1994 10;29(10):923-9.

69. Fidler HM, Thurrell W, Johnson NM, Rook GA, McFadden JJ. Specific detection of mycobacterium paratuberculosis DNA associated with granulomatous tissue in crohn's disease. Gut [Internet]. 1994 04;35(4):506-10.

70. Vannuffel P, Dieterich C, Naerhuyzen B, Gilot P, Coene M, Fiasse R, Cocito C. Occurrence, in crohn's disease, of antibodies directed against a species-specific recombinant polypeptide of mycobacterium paratuberculosis. Clin Diagn Lab Immunol [Internet]. 1994 03;1(2):241-3.

71. Wall S, Kunze ZM, Saboor S, Soufleri I, Seechurn P, Chiodini R, McFadden JJ. Identification of spheroplast-like agents isolated from tissues of patients with crohn's disease and control tissues by polymerase chain reaction. J Clin Microbiol [Internet]. 1993 05;31(5):1241-5.

72. Stainsby KJ, Lowes JR, Allan RN, Ibbotson JP. Antibodies to mycobacterium paratuberculosis and nine species of environmental mycobacteria in crohn's disease and control subjects. Gut [Internet]. 1993 03;34(3):371-4.

73. Moss MT, Sanderson JD, Tizard ML, Hermon-Taylor J, el-Zaatari FA, Markesich DC, Graham DY. Polymerase chain reaction detection of mycobacterium paratuberculosis and mycobacterium avium subsp silvaticum in long term cultures from crohn's disease and control tissues. Gut [Internet]. 1992 09;33(9):1209-13.


74. Sanderson JD, Moss MT, Tizard ML, Hermon-Taylor J. Mycobacterium paratuberculosis DNA in crohn's disease tissue. Gut [Internet]. 1992 07;33(7):890-6.

75. Ebert EC, Bhatt BD, Liu S, Das KM. Induction of suppressor cells by mycobacterium paratuberculosis antigen in inflammatory bowel disease. Clin Exp Immunol [Internet]. 1991 02;83(2):320-5.

76. Tanaka K, Wilks M, Coates PJ, Farthing MJ, Walker-Smith JA, Tabaqchali S. Mycobacterium paratuberculosis and crohn's disease. Gut [Internet]. 1991 01;32(1):43-5.

77. Romero C, Hamdi A, Valentine JF, Naser SA. Evaluation of surgical tissue from patients with crohn's disease for the presence of mycobacterium avium subspecies paratuberculosis DNA by in situ hybridization and nested polymerase chain reaction. Inflamm Bowel Dis [Internet]. 2005 02;11(2):116-25.

78. Butcher PD, McFadden JJ, Hermon-Taylor J. Investigation of mycobacteria in crohn's disease tissue by southern blotting and DNA hybridisation with cloned mycobacterial genomic DNA probes from a crohn's disease isolated mycobacteria. Gut [Internet]. 1988 09;29(9):1222-8.

79. McFadden JJ, Houdayer C. No evidence for antibodies to mycobacterial A60 antigen in crohn's disease sera by enzyme-linked immunoabsorbent assay (ELISA). J Med Microbiol [Internet]. 1988 04;25(4):295-8.

80. Graham DY, Markesich DC, Yoshimura HH. Mycobacteria and inflammatory bowel disease. results of culture. Gastroenterology [Internet]. 1987 02;92(2):436-42.

81. Yoshimura HH, Graham DY, Estes MK, Merkal RS. Investigation of association of mycobacteria with inflammatory bowel disease by nucleic acid hybridization. J Clin Microbiol [Internet]. 1987 01;25(1):45-51.

82. Bull TJ, McMinn EJ, Sidi-Boumedine K, Skull A, Durkin D, Neild P, Rhodes G, Pickup R, Hermon-Taylor J. Detection and verification of mycobacterium avium subsp. paratuberculosis in fresh ileocolonic mucosal biopsy specimens from individuals with and without crohn's disease. J Clin Microbiol [Internet]. 2003 07;41(7):2915-23.

83. Del Prete R, Quaranta M, Lippolis A, Giannuzzi V, Mosca A, Jirillo E, Miragliotta G. Detection of mycobacterium paratuberculosis in stool samples of patients with inflammatory bowel disease by Is900-based pcr and colorimetric detection of amplified dna. J Microbiol Methods [Internet]. 1998 07;33(2):105-14.

84. Clarkston WK, Presti ME, Petersen PF, Zachary PEJ, Fan WX, Leonardi CL, Vernava AM3, Longo WE, Kreeger JM. Role of mycobacterium paratuberculosis in crohn's disease: A prospective, controlled study using polymerase chain reaction. Dis Colon Rectum [Internet]. 1998 02;41(2):195-9.

85. Ellingson JL, Cheville JC, Brees D, Miller JM, Cheville NF. Absence of mycobacterium avium subspecies paratuberculosis components from crohn's disease intestinal biopsy tissues. Clin Med Res [Internet]. 2003 07;1(3):217-26.

86. Schwartz D, Shafran I, Romero C, Piromalli C, Biggerstaff J, Naser N, Chamberlin W, Naser SA. Use of short-term culture for identification of mycobacterium avium subsp. paratuberculosis in tissue from crohn's disease patients. Clin Microbiol Infect [Internet]. 2000 06;6(6):303-7.


87. Cellier C, De Beenhouwer H, Berger A, Penna C, Carbonnel F, Parc R, Cugnenc PH, Le Quintrec Y, Gendre JP, Barbier JP, Portaels F. Mycobacterium paratuberculosis and mycobacterium avium subsp. silvaticum DNA cannot be detected by PCR in crohn's disease tissue. Gastroenterol Clin Biol [Internet]. 1998 09/30;22(8-9):675-8.

88. McFadden J, Collins J, Beaman B, Arthur M, Gitnick G. Mycobacteria in crohn's disease: DNA probes identify the wood pigeon strain of mycobacterium avium and mycobacterium paratuberculosis from human tissue. J Clin Microbiol [Internet]. 1992 12;30(12):3070-3.

89. el-Zaatari FA, Naser SA, Markesich DC, Kalter DC, Engstand L, Graham DY. Identification of mycobacterium avium complex in sarcoidosis. J Clin Microbiol [Internet]. 1996 09;34(9):2240-5.

90. Eishi Y, Suga M, Ishige I, Kobayashi D, Yamada T, Takemura T, Takizawa T, Koike M, Kudoh S, Costabel U, Guzman J, Rizzato G, Gambacorta M, du Bois R, Nicholson AG, Sharma OP, Ando M. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of japanese and european patients with sarcoidosis. J Clin Microbiol [Internet]. 2002 01;40(1):198-204.

91. Bitti ML, Masala S, Capasso F, Rapini N, Piccinini S, Angelini F, Pierantozzi A, Lidano R, Pietrosanti S, Paccagnini D, Sechi LA. Mycobacterium avium subsp. paratuberculosis in an italian cohort of type 1 diabetes pediatric patients. [Internet]. 2012;2012:785262.

92. Cossu A, Ferrannini E, Fallahi P, Antonelli A, Sechi LA. Antibodies recognizing specific mycobacterium avium subsp. paratuberculosis's MAP3738c protein in type 1 diabetes mellitus children are associated with serum Th1 (CXCL10) chemokine. [Internet]. 2013;61(2):337-9.

93. Rosu V, Ahmed N, Paccagnini D, Gerlach G, Fadda G, Hasnain SE, Zanetti S, Sechi LA. Specific immunoassays confirm association of mycobacterium avium subsp. paratuberculosis with type-1 but not type-2 diabetes mellitus. PLoS One [Internet]. 2009;4(2):e4386.

94. Rosu V, Ahmed N, Paccagnini D, Pacifico A, Zanetti S, Sechi LA. Mycobacterium avium subspecies paratuberculosis is not associated with type-2 diabetes mellitus. Ann Clin Microbiol Antimicrob [Internet]. 2008;7:9.

95. Richter E, Wessling J, Lugering N, Domschke W, Rusch-Gerdes S. Mycobacterium avium subsp. paratuberculosis infection in a patient with HIV, germany. Emerging Infect Dis [Internet]. 2002 07;8(7):729-31.

96. Lisby G, Milman N, Jacobsen GK. Search for mycobacterium paratuberculosis DNA in tissue from patients with sarcoidosis by enzymatic gene amplification. APMIS [Internet]. 1993 11;101(11):876-8.

97. Markesich DC, Sawai ET, Butel JS, Graham DY. Investigations on etiology of crohn's disease. humoral immune response to stress (heat shock) proteins. Dig Dis Sci [Internet]. 1991 04;36(4):454-60.

98. Nakase H, Nishio A, Tamaki H, Matsuura M, Asada M, Chiba T, Okazaki K. Specific antibodies against recombinant protein of insertion element 900 of mycobacterium avium subspecies paratuberculosis in japanese patients with crohn's disease. Inflamm Bowel Dis [Internet]. 2006 01;12(1):62-9.

99. Dalton HR, Hoang P, Jewell DP. Antigen induced suppression in peripheral blood and lamina propria mononuclear cells in inflammatory bowel disease. Gut [Internet]. 1992 03;33(3):324-30.


100. Bernstein CN, Wang MH, Sargent M, Brant SR, Collins MT. Testing the interaction between NOD-2 status and serological response to mycobacterium paratuberculosis in cases of inflammatory bowel disease. J Clin Microbiol [Internet]. 2007 03;45(3):968-71.

101. Bibiloni R, Mangold M, Madsen KL, Fedorak RN, Tannock GW. The bacteriology of biopsies differs between newly diagnosed, untreated, crohn's disease and ulcerative colitis patients. J Med Microbiol [Internet]. 2006 08;55(8):1141-9. Available from: http://www.socgenmicrobiol.org.uk/default.htm CCC:000239827800023

102. Cheng J, Bull TJ, Dalton P, Cen S, Finlayson C, Hermon-Taylor J. Mycobacterium avium subspecies paratuberculosis in the inflamed gut tissues of patients with crohn's disease in china and its potential relationship to the consumption of cow's milk: A preliminary study. World J Microbiol Biotechnol [Internet]. 2005 10;21(6-7):1175-9. Available from: Error! Hyperlink reference not valid.

103. Clancy R, Ren Z, Turton J, Pang G, Wettstein A. Molecular evidence for mycobacterium avium subspecies paratuberculosis (MAP) in crohn's disease correlates with enhanced TNF-alpha secretion. Dig Liver Dis [Internet]. 2007 05;39(5):445-51.

104. Lozano-Leon A, Barreiro-de Acosta, Dominguez-Munoz JE. Absence of mycobacterium avium subspecies paratuberculosis in crohn's disease patients. Inflamm Bowel Dis [Internet]. 2006 12;12(12):1190-2.

105. Scanu AM, Bull TJ, Cannas S, Sanderson JD, Sechi LA, Dettori G, Zanetti S, Hermon-Taylor J. Mycobacterium avium subspecies paratuberculosis infection in cases of irritable bowel syndrome and comparison with crohn's disease and johne's disease: Common neural and immune pathogenicities. J Clin Microbiol [Internet]. 2007 12;45(12):3883-90.

106. Sechi LA, Gazouli M, Sieswerda LE, Molicotti P, Ahmed N, Ikonomopoulos J, Scanu AM, Paccagnini D, Zanetti S. Relationship between crohn's disease, infection with mycobacterium avium subspecies paratuberculosis and SLC11A1 gene polymorphisms in sardinian patients. World J Gastroenterol [Internet]. 2006 11/28;12(44):7161-4.

107. Sechi LA, Gazouli M, Ikonomopoulos J, Lukas JC, Scanu AM, Ahmed N, Fadda G, Zanetti S. Mycobacterium avium subsp. paratuberculosis, genetic susceptibility to crohn's disease, and sardinians: The way ahead. J Clin Microbiol [Internet]. 2005 10;43(10):5275-7.

108. Cossu D, Cocco E, Paccagnini D, Masala S, Ahmed N, Frau J, Marrosu MG, Sechi LA. Association of mycobacterium avium subsp. paratuberculosis with multiple sclerosis in sardinian patients. PLoS One [Internet]. 2011 Apr 13;6(4):e18482.

109. Cossu D, Masala S, Cocco E, Paccagnini D, Frau J, Marrosu MG, Sechi LA. Are mycobacterium avium subsp. paratuberculosis and epstein-barr virus triggers of multiple sclerosis in sardinia? Mult Scler [Internet]. 2012 Aug;18(8):1181-4.

110. Cossu D, Masala S, Cocco E, Paccagnini D, Tranquilli S, Frau J, Marrosu MG, Sechi LA. Association of mycobacterium avium subsp. paratuberculosis and SLC11A1 polymorphisms in sardinian multiple sclerosis patients. J Infect Dev Ctries [Internet]. 2013 Mar 14;7(3):203-7.

111. Cossu D, Masala S, Frau J, Cocco E, Marrosu MG, Sechi LA. Anti mycobacterium avium subsp. paratuberculosis heat shock protein 70 antibodies in the sera of sardinian patients with multiple sclerosis. J Neurol Sci [Internet]. 2013 Dec 15;335(1-2):131-3.


http://www.socgenmicrobiol.org.uk/default.htm%20CCC:000239827800023

http://www.socgenmicrobiol.org.uk/default.htm%20CCC:000239827800023

112. Frau J, Cossu D, Coghe G, Lorefice L, Fenu G, Melis M, Paccagnini D, Sardu C, Murru MR, Tranquilli S, Marrosu MG, Sechi LA, Cocco E. Mycobacterium avium subsp. paratuberculosis and multiple sclerosis in sardinian patients: Epidemiology and clinical features. Mult Scler [Internet]. 2013 Oct;19(11):1437-42.

113. D'Amore M, Lisi S, Sisto M, Cucci L, Dow CT. Molecular identification of mycobacterium avium subspecies paratuberculosis in an italian patient with hashimoto's thyroiditis and melkersson-rosenthal syndrome. J Med Microbiol [Internet]. 2010 Jan;59(Pt 1):137-9.

114. Sisto M, Cucci L, D'Amore M, Dow TC, Mitolo V, Lisi S. Proposing a relationship between mycobacterium avium subspecies paratuberculosis infection and hashimoto's thyroiditis. Scand J Infect Dis [Internet]. 2010 Oct;42(10):787-90.

115. Pistone D, Marone P, Pajoro M, Fabbi M, Vicari N, Daffara S, Dalla Valle C, Gabba S, Sassera D, Verri A, Montagna M, Epis S, Monti C, Strada EG, Grazioli V, Arrigoni N, Giacosa A, Bandi C. Mycobacterium avium paratuberculosis in italy: Commensal or emerging human pathogen? Dig Liver Dis [Internet]. 2012 Jun;44(6):461-5.

116. Naser SA, Schwartz D, Shafran I. Isolation of mycobacterium avium subsp paratuberculosis from breast milk of crohn's disease patients. Am J Gastroenterol [Internet]. 2000 04;95(4):1094-5.

117. Singh SV, Sohal JS, Singh PK, Singh AV. Genotype profiles of mycobacterium avium subspecies paratuberculosis isolates recovered from animals, commercial milk, and human beings in north india. Int J Infect Dis [Internet]. 2009 09;13(5):e221-7.

118. Singh AV, Singh SV, Sohal JS, Singh PK. Genotype profiles of mycobacterium avium subspecies paratuberculosis recovered from suspected and crohn's disease patients in india. [Internet]. 2010;42(2):91-100. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-78149434803&partnerID=40&md5=cae1663a94d27965bac2ff781737749c

119. Wagner J, Sim W, Bishop RF, Catto-Smith AG, Cameron DJ, Kirkwood CD. Mycobacterium avium subspecies paratuberculosis in children with early-onset crohn's disease: A longitudinal follow-up study. Inflamm Bowel Dis [Internet]. 2011 01/06

120. Jones PH, Farver TB, Beaman B, Cetinkaya B, Morgan KL. Crohn's disease in people exposed to clinical cases of bovine paratuberculosis. Epidemiol Infect [Internet]. 2006 02;134(1):49-56.

121. Qual DA, Kaneene JB, Varty TJ, Miller R, Thoen CO. Lack of association between the occurrence of crohn's disease and occupational exposure to dairy and beef cattle herds infected with mycobacterium avium subspecies paratuberculosis. J Dairy Sci [Internet]. 2010 06;93(6):2371-6.

122. Gitnick G, Collins J, Beaman B, Brooks D, Arthur M, Imaeda T, Palieschesky M. Preliminary report on isolation of mycobacteria from patients with crohn's disease. Dig Dis Sci [Internet]. 1989 06;34(6):925-32.

123. Van Kruiningen HJ, Chiodini RJ, Thayer WR, Coutu JA, Merkal RS, Runnels PL. Experimental disease in infant goats induced by a mycobacterium isolated from a patient with crohn's disease. A preliminary report. Dig Dis Sci [Internet]. 1986 12;31(12):1351-60.

124. Wynne JW, Bull TJ, Seemann T, Bulach DM, Wagner J, Kirkwood CD, Michalski WP. Exploring the zoonotic potential of mycobacterium avium subspecies paratuberculosis through comparative genomics. [Internet]. 2011;6(7):e22171.


http://www.scopus.com/inward/record.url?eid=2-s2.0-78149434803&partnerID=40&md5=cae1663a94d27965bac2ff781737749c

http://www.scopus.com/inward/record.url?eid=2-s2.0-78149434803&partnerID=40&md5=cae1663a94d27965bac2ff781737749c

125. Whittington RJ, Hope AF, Marshall DJ, Taragel CA, Marsh I. Molecular epidemiology of mycobacterium avium subsp. paratuberculosis: IS900 restriction fragment length polymorphism and IS1311 polymorphism analyses of isolates from animals and a human in australia. J Clin Microbiol [Internet]. 2000 09;38(9):3240-8.

126. Ghadiali AH, Strother M, Naser SA, Manning EJ, Sreevatsan S. Mycobacterium avium subsp. paratuberculosis strains isolated from crohn's disease patients and animal species exhibit similar polymorphic locus patterns. J Clin Microbiol [Internet]. 2004 11;42(11):5345-8.

127. Motiwala AS, Strother M, Amonsin A, Byrum B, Naser SA, Stabel JR, Shulaw WP, Bannantine JP, Kapur V, Sreevatsan S. Molecular epidemiology of mycobacterium avium subsp. paratuberculosis: Evidence for limited strain diversity, strain sharing, and identification of unique targets for diagnosis. J Clin Microbiol [Internet]. 2003 05;41(5):2015-26.

128. Francois B, Krishnamoorthy R, Elion J. Comparative study of mycobacterium paratuberculosis strains isolated from crohn's disease and johne's disease using restriction fragment length polymorphism and arbitrarily primed polymerase chain reaction. Epidemiol Infect [Internet]. 1997 06;118(3):227-33.

129. Reid JD, Chiodini RJ. Serologic reactivity against mycobacterium paratuberculosis antigens in patients with sarcoidosis. Sarcoidosis [Internet]. 1993 03;10(1):32-5.

130. Ikonomopoulos JA, Gorgoulis VG, Kastrinakis NG, Zacharatos PV, Kokotas SN, Evangelou K, Kotsinas AG, Tsakris AG, Manolis EN, Kittas CN. Sensitive differential detection of genetically related mycobacterial pathogens in archival material. Am J Clin Pathol [Internet]. 2000 12;114(6):940-50.

131. Cho SN, Brennan PJ, Yoshimura HH, Korelitz BI, Graham DY. Mycobacterial aetiology of crohn's disease: Serologic study using common mycobacterial antigens and a species-specific glycolipid antigen from mycobacterium paratuberculosis. Gut [Internet]. 1986 11;27(11):1353-6.

132. Chiba M, Kono M, Hoshina S, Komatsu M, Kitagawa Y, Iizuka M, Watanabe S. Presence of bacterial 16S ribosomal RNA gene segments in human intestinal lymph follicles. Scand J Gastroenterol [Internet]. 2000 08;35(8):824-31.

133. Brunello F, Pera A, Martini S, Marino L, Astegiano M, Barletti C, Gastaldi P, Verme G, Emanuelli G. Antibodies to mycobacterium paratuberculosis in patients with crohn's disease. Dig Dis Sci [Internet]. 1991 12;36(12):1741-5.

134. Thayer WRJ, Coutu JA, Chiodini RJ, Van Kruiningen HJ, Merkal RS. Possible role of mycobacteria in inflammatory bowel disease. II. mycobacterial antibodies in crohn's disease. Dig Dis Sci [Internet]. 1984 12;29(12):1080-5.

135. Baksh FK, Finkelstein SD, Ariyanayagam-Baksh SM, Swalsky PA, Klein EC, Dunn JC. Absence of mycobacterium avium subsp. paratuberculosis in the microdissected granulomas of crohn's disease. Mod Pathol [Internet]. 2004 10;17(10):1289-94.

136. Pierce ES, Borowitz SM, Naser SA. The broad street pump revisited: Dairy farms and an ongoing outbreak of inflammatory bowel disease in forest, virginia. [Internet]. 2011;3(1):20, 4749,3-20.

137. Wagner J, Skinner NA, Catto-Smith AG, Cameron DJ, Michalski WP, Visvanathan K, Kirkwood CD. TLR4, IL10RA, and NOD2 mutation in paediatric crohn's disease patients: An association with


mycobacterium avium subspecies paratuberculosis and TLR4 and IL10RA expression. [Internet]. 2013;202(4):267-76.

138. Riggio MP, Gibson J, Lennon A, Wray D, MacDonald DG. Search for mycobacterium paratuberculosis DNA in orofacial granulomatosis and oral crohn's disease tissue by polymerase chain reaction. Gut [Internet]. 1997 11;41(5):646-50.

139. Singh UP, Singh R, Singh S, Karls RK, Quinn FD, Taub DD, Lillard JWJ. CXCL10+ T cells and NK cells assist in the recruitment and activation of CXCR3+ and CXCL11+ leukocytes during mycobacteria-enhanced colitis. BMC Immunol [Internet]. 2008;9:25.

140. Jeyanathan M, Boutros-Tadros O, Radhi J, Semret M, Bitton A, Behr MA. Visualization of mycobacterium avium in crohn's tissue by oil-immersion microscopy. Microbes Infect [Internet]. 2007 12/31;9(14-15):1567-73.

141. Toracchio S, El-Zimaity HM, Urmacher C, Katz S, Graham DY. Mycobacterium avium subspecies paratuberculosis and crohn's disease granulomas. Scand J Gastroenterol [Internet]. 2008;43(9):1108-11.

142. Rocca S, Cubeddu T, Nieddu AM, Pirino S, Appino S, Antuofermo E, Tanda F, Verin R, Sechi LA, Taccini E, Leoni A. Detection of mycobacterium avium spp. paratuberculosis (map) in samples of sheep paratuberculosis (johne's disease or JD) and human crohn's disease (CD) using liquid phase RT-PCR, in situ RT-PCR and immunohistochemistry. [Internet]. 2010;88(2-3):126-34. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-75749147094&partnerID=40&md5=467e25c97ef5c74bbddacb69fe4271c7

143. Valentine JF, Elam J, Naser SA. Atg16l1 (autophagy-related 16-like 1) crohn's disease (cd) associated snp is not associated with viable mycobacterium avium subspecies paratuberculosis (map) in the blood of cd patients. Gastroenterology. 2008;134(4)

144. Bernstein CN, Rawsthorne P, Cheang M, Blanchard JF. A population-based case control study of potential risk factors for IBD. Am J Gastroenterol [Internet]. 2006 05;101(5):993-1002.


http://www.scopus.com/inward/record.url?eid=2-s2.0-75749147094&partnerID=40&md5=467e25c97ef5c74bbddacb69fe4271c7

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Appendix- Meta-analysis Forest Plots and Meta-Regression results presented in the tables 1-4 of the zoonotic potential of M. paratuberculosis – SR-MA.Forest Plots were generated by Comprehensive Meta-analysis

Meta-regression was conducted in STATA 13.

Forest Plots from Table 1 in the manuscript:

Figure S1: Random effect meta-analysis of 15 studies that used culture or staining to identify M. paratuberculosis in samples from Crohn’s disease patients ( I2= 41.6%).

Study name Method_1 Author Time point Statistics for each study Odds ratio and 95% CI

Odds Lower Upper ratio limit limit p-Value

430-2005 culture Kreuzpaintner 1995 51.09 2.77 940.96 0.01141b-2005 culture Naser 2004 11.00 2.16 55.92 0.002945b-2005 culture Sechi 2005 16.12 3.96 65.59 0.001230 culture Chamberlin 2008 15.38 0.78 304.07 0.07280a culture Ricanek 2010 2.92 0.40 21.09 0.29280b culture Ricanek 2010 23.57 1.21 457.36 0.0410113b culture Singh 2011 7.00 2.40 20.39 0.00519-2005 culture-PCR McFadden 1992 6.28 0.25 159.45 0.27630b-2005 culture-PCR Del Prete 1998 3.44 1.08 10.97 0.0440-2005 culture-PCR Schwartz 2000 10.00 1.97 50.83 0.01541-2005 culture-PCR Naser 2000 55.00 0.83 3650.69 0.066b-2005 culture-PCR Bull 2003 7.37 1.87 29.08 0.001260c culture-PCR Singh 2008 8.00 0.79 81.33 0.08610a culture-PCR Kirkwood 2009 9.00 0.40 203.30 0.17280c culture-PCR Ricanek 2010 0.95 0.04 23.50 0.97280d culture-PCR Ricanek 2010 10.00 0.75 132.68 0.08320b culture-PCR Mendoza 2010 1565.67 61.58 39804.92 0.0040 b culture-PCR Rath 2011 0.24 0.03 1.97 0.1810113a staining Singh 2011 31.45 1.83 541.60 0.02

8.44 4.51 15.83 0.00

0.01 0.1 1 10 100

Figure S2: Random effect meta-analysis of 40 studies that used PCR or hybridization to identify M. paratuberculosis in samples from Crohn’s disease patients ( I2= 83.3%).


Study name Method_1 Sample_1 Author Time point Statistics for each study Odds ratio and 95% CI


272b-2005 hybridization tissue Hulten 2001 4.783 0.927 24.671 0.06155-2005a hybridization tissue Romero 2005 32.111 1.487 693.488 0.027162a-2005 hybridization tissue Sechi 2004 626.684 35.548 11048.022 0.000595-2005 hybridization tissue Yoshimura 1987 3.333 0.682 16.295 0.1371210 PCR blood Bentley 2008 1.864 1.247 2.785 0.00220 d PCR blood Di Sabatino 2011 8.727 4.498 16.933 0.00010053 PCR blood Elguezabal 2012 0.487 0.315 0.752 0.001910b PCR blood Juste 2009 0.427 0.238 0.766 0.004610c PCR blood Kirkwood 2009 5.143 1.037 25.501 0.045141a-2005 PCR blood Naser 2004 2.105 0.665 6.658 0.205860 PCR blood Parrish 2009 0.331 0.013 8.195 0.499524-2005 PCR blood Sanderson 1992 17.643 6.095 51.072 0.000630a-2005 PCR feces Del Prete 1998 5.118 1.949 13.441 0.00170 PCR feces Imirzalioglu 2011 50.480 9.709 262.464 0.00010113c PCR feces Singh 2011 1.200 0.110 13.146 0.88130 PCR feces Tuci 2011 1.663 0.634 4.359 0.3012862-2005 PCR tissue Autschbach 2005 29.869 12.766 69.887 0.000172-2005 PCR tissue Bernstein 2003 0.135 0.007 2.456 0.1766a- 2005 PCR tissue Bull 2003 31.481 7.725 128.301 0.000259-2008 PCR tissue Cheng 2005 13.500 2.010 90.689 0.00758-2008 PCR tissue Clancy 2007 1.927 0.936 3.969 0.075654b-2005 PCR tissue Clarkston 1998 2.415 0.092 63.253 0.597234d-2005 PCR tissue Collins 2000 0.987 0.465 2.094 0.97212-2005 PCR tissue Dell'Isola 1994 7.511 2.088 27.014 0.002474-2005 PCR tissue Fidler 1994 9.982 0.514 193.953 0.129272a-2005 PCR tissue Hulten 2001 4.286 1.064 17.259 0.041610b PCR tissue Kirkwood 2009 4.992 1.925 12.941 0.001150b PCR tissue Lee 2011 9.962 1.831 54.190 0.008150c PCR tissue Lee 2011 46.250 4.272 500.729 0.002461-2005 PCR tissue Lisby 1994 4.701 1.633 13.536 0.004408-2005 PCR tissue Mishina 1996 17.000 0.598 483.500 0.09710019 PCR tissue Molicotti 2013 20.000 1.850 216.178 0.014523-2005 PCR tissue Moss 1992 5.000 0.513 48.750 0.166314-2005 PCR tissue Murray 1995 4.000 0.476 33.585 0.20210008-2013 PCR tissue Pistone 2012 5.897 2.310 15.058 0.0001300b PCR tissue Ren 2008 2.392 0.915 6.252 0.07555-2005b PCR tissue Romero 2005 8.333 1.034 67.142 0.046441-2005 PCR tissue Rowbotham 1995 0.363 0.015 9.050 0.537205-2005 PCR tissue Ryan 2002 17.105 0.854 342.744 0.06335-2008 PCR tissue Scanu 2007 8.148 2.083 31.875 0.003122-2008 PCR tissue Sechi 2005 8.036 2.731 23.645 0.000162b-2005 PCR tissue Sechi 2004 13.028 0.748 226.929 0.0782945a-2005 PCR tissue Sechi 2005 46.667 10.109 215.426 0.00044-2005 PCR tissue Suenaga 1995 7.824 0.416 146.989 0.169495-2005 PCR tissue Wall 1993 2.826 0.117 68.302 0.523

5.239 3.329 8.245 0.000

0.01 0.1 1 10 100

Figure S3: Random effect meta-analysis of studies that used PCR, sub grouped by primers used to identify M. paratuberculosis in samples from Crohn’s disease patients ( I2= 0% except for primers [p89/p92] 41.1% and [p90/p91] 51.7%).


Study name Author Time point Sample_1 Group byPrimers

Statistics for each study Odds ratio and 95% CI


44-2005 Suenaga 1995 tissue [IS1/IS2] 7.824 0.416 146.989 0.169 [IS1/IS2] 7.824 0.334 183.084 0.201

1210 Bentley 2008 blood [SF214, SR289] 1.864 1.247 2.785 0.002 [SF214, SR289] 1.864 0.548 6.337 0.319

474-2005 Fidler 1994 tissue [1/2] 9.982 0.514 193.953 0.129408-2005 Mishina 1996 tissue [1/2] 17.000 0.598 483.500 0.097495-2005 Wall 1993 tissue [1/2] 2.826 0.117 68.302 0.523

[1/2] 7.742 1.111 53.922 0.039630a-2005 Del Prete 1998 feces [150C/921] 5.118 1.949 13.441 0.00110113c Singh 2011 feces [150C/921] 1.200 0.110 13.146 0.88112-2005 Dell'Isola 1994 tissue [150C/921] 7.511 2.088 27.014 0.002

[150C/921] 4.710 1.659 13.371 0.00430 Tuci 2011 feces [MapF, MapR] 1.663 0.634 4.359 0.301

[MapF, MapR] 1.663 0.369 7.490 0.50870 Imirzalioglu 2011 feces [P3N, P4N] 50.480 9.709 262.464 0.000

[P3N, P4N] 50.480 6.740 378.060 0.000122-2008 Sechi 2005 tissue [p89/p92] 8.036 2.731 23.645 0.000162b-2005 Sechi 2004 tissue [p89/p92] 13.028 0.748 226.929 0.0782945a-2005 Sechi 2005 tissue [p89/p92] 46.667 10.109 215.426 0.000

[p89/p92] 15.882 5.108 49.381 0.000141a-2005 Naser 2004 blood [P90/P91] 2.105 0.665 6.658 0.205524-2005 Sanderson 1992 blood [P90/P91] 17.643 6.095 51.072 0.000654b-2005 Clarkston 1998 tissue [P90/P91] 2.415 0.092 63.253 0.597272a-2005 Hulten 2001 tissue [P90/P91] 4.286 1.064 17.259 0.041523-2005 Moss 1992 tissue [P90/P91] 5.000 0.513 48.750 0.166441-2005 Rowbotham 1995 tissue [P90/P91] 0.363 0.015 9.050 0.537

[P90/P91] 4.508 1.941 10.470 0.000234d-2005 Collins 2000 tissue [PBT5/PBT12] 0.987 0.465 2.094 0.972

[PBT5/PBT12] 0.987 0.248 3.920 0.985314-2005 Murray 1995 tissue [TDB3/TDB4] 4.000 0.476 33.585 0.202

[TDB3/TDB4] 4.000 0.355 45.053 0.262205-2005 Ryan 2002 tissue not stated 17.105 0.854 342.744 0.063

not stated 17.105 0.688 425.036 0.083

0.01 0.1 1 10 100

Figure S4: Random effect meta-analysis of studies that used nested PCR, sub grouped by primers used to identify M. paratuberculosis in samples from Crohn’s disease patients ( I2= 0% except for primers [liz1, liz2][AV1, AV2] 78.0% and [p90/p91][AV1, AV2] 62.78%).


Study name Author Time point Sample_1 Group byPrimers

Statistics for each study Odds ratio and 95% CI


2862-2005 Autschbach 2005 tissue [Liz1, Liz2] [AV1, AV2] 29.869 12.766 69.887 0.0006a- 2005 Bull 2003 tissue [Liz1, Liz2] [AV1, AV2] 31.481 7.725 128.301 0.000259-2008 Cheng 2005 tissue [Liz1, Liz2] [AV1, AV2] 13.500 2.010 90.689 0.00758-2008 Clancy 2007 tissue [Liz1, Liz2] [AV1, AV2] 1.927 0.936 3.969 0.075150b Lee 2011 tissue [Liz1, Liz2] [AV1, AV2] 9.962 1.831 54.190 0.008150c Lee 2011 tissue [Liz1, Liz2] [AV1, AV2] 46.250 4.272 500.729 0.00210019 Molicotti 2013 tissue [Liz1, Liz2] [AV1, AV2] 20.000 1.850 216.178 0.0141300b Ren 2008 tissue [Liz1, Liz2] [AV1, AV2] 2.392 0.915 6.252 0.07535-2008 Scanu 2007 tissue [Liz1, Liz2] [AV1, AV2] 8.148 2.083 31.875 0.003

[Liz1, Liz2] [AV1, AV2] 9.803 4.537 21.177 0.000172-2005 Bernstein 2003 tissue [P90/P91] [AV1/AV2] 0.135 0.007 2.456 0.17610053 Elguezabal 2012 blood [P90/P91] [AV1/AV2] 0.487 0.315 0.752 0.001910b Juste 2009 blood [P90/P91] [AV1/AV2] 0.427 0.238 0.766 0.00455-2005b Romero 2005 tissue [P90/P91] [AV1/AV2] 8.333 1.034 67.142 0.046

[P90/P91] [AV1/AV2] 0.649 0.211 1.998 0.451860 Parrish 2009 blood [P90/P91] [TJ1, TJ2] 0.331 0.013 8.195 0.499

[P90/P91] [TJ1, TJ2] 0.331 0.008 13.087 0.555461-2005 Lisby 1994 tissue [PTB1 PTB2] [PTB5 PTB12] 4.701 1.633 13.536 0.004

[PTB1 PTB2] [PTB5 PTB12] 4.701 0.585 37.779 0.14510008-2013 Pistone 2012 tissue [S1/ R3,S2/ R1], [F57/R57, F57rn] 5.897 2.310 15.058 0.000

[S1/ R3,S2/ R1], [F57/R57, F57rn] 5.897 0.778 44.704 0.086610b Kirkwood 2009 tissue [TJ1, TJ2 ] 4.992 1.925 12.941 0.001610c Kirkwood 2009 blood [TJ1, TJ2 ] 5.143 1.037 25.501 0.045

[TJ1, TJ2 ] 5.054 1.070 23.875 0.04120 d Di Sabatino 2011 blood not stated 8.727 4.498 16.933 0.000

not stated 8.727 1.287 59.174 0.027

0.01 0.1 1 10 100

Figure S5: Random effect meta-analysis of 4 studies that used hybridization to identify M. paratuberculosis in samples from Crohn’s disease patients (I2= 73.0%).

Study name Author Time point Sample_1 Statistics for each study Odds ratio and 95% CI


272b-2005 Hulten 2001 tissue 4.783 0.927 24.671 0.061

55-2005a Romero 2005 tissue 32.111 1.487 693.488 0.027

162a-2005 Sechi 2004 tissue 626.684 35.548 11048.022 0.000

595-2005 Yoshimura 1987 tissue 3.333 0.682 16.295 0.137

9.190 3.374 25.029 0.000

0.01 0.1 1 10 100


Table S1: Meta-regression of PCR and hybridization results with the origin of the samples significantly explaining 33% of the heterogeneity between these studies. The referent group is hospital samples.

Meta-regression Number of obs = 45REML estimate of between-study variance tau2 = .8914% residual variation due to heterogeneity I-squared_res = 68.18%Proportion of between-study variance explained Adj R-squared = 33.05%Joint test for all covariates Model F(4,40) = 4.53With Knapp-Hartung modification Prob > F = 0.0041--------------------------------------------------------------------------------------------- logor | Coef. Std. Err. t P>|t| [95% Conf. Interval]--------------+------------------------------------------------------------------------------Clinic | -1.907897 .568178 -3.36 0.002 -3.056227 -.7595663Gen Popn | -1.903139 .7855581 -2.42 0.020 -3.490811 -.3154666Library | .3268261 .5071357 0.64 0.523 -.6981334 1.351786ND | -.2695806 .7076707 -0.38 0.705 -1.699836 1.160675_cons | 1.955215 .2574111 7.60 0.000 1.434968 2.475462-------------------------------------------------------------------------------

Table S2: This is the odds ratios exponentiated from the meta-regression model above for each sample origin group.

OR 95% Conf. Interval

hospital 7.07 4.27 11.70

clinic 1.05 0.34 3.19

general population 1.05 0.22 4.91

library 9.72 3.63 26.47

nd 5.35 1.35 19.85



Figure S6: Random effect meta-analysis of 2 studies that used SDS-immunoblot to identify M. paratuberculosis reaction in samples from Crohn’s disease patients (I2= 42.5%).

Study name Author Time point Antigen Statistics for each study Odds ratio and 95% CI


329-2005 El-Zaatari 1999 PPD- p36 13.750 6.635 28.495 0.00

288-2005b Naser 2000 PPD- p35 20.000 6.907 57.909 0.00

288-2005c Naser 2000 PPD- p36 47.400 18.954 118.539 0.00

288-2005a Naser 2000 PPD- p 35 &p36 59.280 7.889 445.428 0.00

25.011 12.549 49.849 0.00

0.010.1 1 10 100



Figure S7: Random effect meta-analysis of5 studies sub grouped by ELISA results and PCR results for an association with M. paratuberculosis and type 1 diabetes patients (I2= ELISA 50.5% and PCR 31%).

Study name Group byMethod1

Antigen Author Time point Statistics for each study Odds ratio and 95% CIOdds Lower Upper

ratio limit limit p-Value

10003a ELISA antigen HbHA Bitti 2012 9.333 3.657 23.821 0.00010082 ELISA anti-MAP3865c Abs Masala 2012 9.232 2.884 29.555 0.00010086a ELISA Anti MAP-IgG Naser 2013 2.000 0.244 16.362 0.51810245 cSV ELISA antigen HbHA Rosu 2009 25.781 8.287 80.204 0.00010245a SV ELISA fMptD Rosu 2009 6.210 2.674 14.424 0.00010245b SV ELISA MptD Rosu 2009 16.363 3.600 74.376 0.00010245d SV ELISA cell lysates Rosu 2009 28.627 10.454 78.396 0.00010245f SV ELISA GSD protein Rosu 2009 4.683 2.092 10.481 0.000

ELISA 9.948 5.810 17.032 0.00010003b PCR - Bitti 2012 2.903 1.095 7.697 0.03210086b PCR - Naser 2013 0.429 0.053 3.483 0.42810176 SV PCR - Paccagnini 2009 4.301 2.062 8.972 0.00010245e SV PCR - Rosu 2009 6.176 0.260 146.777 0.260

PCR 2.825 1.210 6.595 0.016

0.01 0.1 1 10 100

Figure S8: Random effect meta-analysis of 2 studies that used ELISA to identify M. paratuberculosis reaction in samples from Multiple sclerosis patients from Sardinia, Italy (I2= 70%).

Study name Author Time point method 1 Statistics for each study Odds ratio and 95% CIOdds Lower Upper

ratio limit limit Z-Value p-Value

10005-2013 Frau 2013 ELISA 10.013 5.147 19.480 6.786 0.000

10007-2013 Cossu 2013 ELISA 4.334 2.390 7.861 4.828 0.000

6.498 2.861 14.757 4.472 0.000

0.010.1 1 10 100


Systematic Review ProtocolSeptember 2013

“The Zoonotic Potential of Mycobacterium avium ssp. Paratuberculosis,

a Systematic Review- Meta-Analysis”

Update Project Team:

Lisa Waddell, principal investigator/ project administrator

Dr. Andrijana Rajić, Scott Mc Ewen, Katharina Stärk

This systematic review protocol describes the changes since the original SR (waddell 2008) and has a copy of all relevant tools. If further details from the original protocol are required, please contact L. Waddell at [email protected] .

Amendments to original protocol:

3.2 The review will be managed locally using Procite1 and Microsoft excel, the forms have been slightly modified to reflect the narrowed scope of the updated SR (only zoonotic potential, not sources) and adjustments to the assessment of bias in articles as more validated tools are available from GRADE.

3.3 Based on the findings of Nyugen et al (2007)3, the three databases will be searched for the update including Pubmed, Scopus (changed from agricola as this is more relevant) and Current Contents for articles published from May 2008 to present.

3.5 Five literature reviews captured in this updated search will be randomly selected using a random number generator to examine the reference lists as a search verification procedure. We will also verify the relevance of studies captured in other systematic reviews published on M. Paratuberculosis (4-6). This protocol was found to be most effective by Nyugen et al. (2007).

We will not hand search conference proceedings or government websites for new unpublished research. This exercise has not netted us good information, which can contribute to the systematic review in the past.

3.7-3.8 Relevance screening 1 and 2 will be combined into one screening stage.

3.9 A GRADE strategy will be implement, see below for the strategy. All papers included in the 2005 SR will be “GRADEed”.


mailto:[email protected]

Search:

Implemented in Pubmed, Scopus and Current Contents: September 27, 2013.*Note other search strings not implemented as they have been covered by the Scoping Review that is occurring simultaneously.

Search string “human disease and Johne’s Disease/Paratuberculosis” implemented January 2005- present.

((johne disease) OR (johne’s disease) OR (johne* disease) OR paratuberculosis OR (mycobacterium paratuberculosis) Or (mycobacteria AND crohn*))

AND

((crohn* disease) OR (crohn disease) OR (crohn’s disease) OR (inflammatory bowel disease) OR (inflammatory bowel diseases) OR diabetes OR sarcoidosis OR lymphadenitis OR immunocompromis*

OR (AIDS) OR (Blau syndrome) OR (multiple sclerosis) OR thyroiditis)

Search string “human disease except crohn’s and Johne’s disease/Paratuberculosis” implemented for capture pre 2005 to verify none were missed in previous systematic review.

((johne disease) OR (johne’s disease) OR (johne* disease) OR paratuberculosis OR (mycobacterium paratuberculosis) Or (mycobacteria AND crohn*))

AND

(diabetes OR sarcoidosis OR lymphadenitis OR immunocompromis* OR (AIDS) OR (Blau syndrome) OR (multiple sclerosis) OR thyroiditis)

Verification

The verification strategy is 2-fold.

1) The scoping review will be identifying all relevant citations for this question independently.

a. All potentially relevant primary citations in English will be compared to what has been captured/screened in the SR. Any potentially relevant citations will be screened by 2 people using the SR tools.

2) The reference lists of the 5 most recent literature reviews will be evaluated for missing citations.

a. The reference lists of 5 lit reviews were evaluated (randomly selected from potentially relevant reviews published in 2010 and 2011) and all potentially relevant citations were cross checked with all previous databases and the ScS database to see if it had been screened. If not a list was compiled and the references were screened by two reviewers using the tools.

List of 5 Literature Reviews evaluated:


Refid Reference Year

10078

Lalande, J. D. and Behr, M. A.. Mycobacteria in Crohn's disease: how innate immune deficiency may result in chronic inflammation. Expert Rev Clin Immunol. 2010. 4 (6):# 2010

10118

Sohal, J. S., Singh, S. V., Singh, A. V., and Singh, P. K.. Strain diversity within Mycobacterium avium subspecies paratuberculosis--a review. Indian J Exp Biol. 2010. 1 (48):#startpage. 2010

12130

Kaevska, M. and Hruska, K.. Analysis of publications on paratuberculosis from 1995 to 2009 with emphasis on the period from 2005 to 2009. 2010. #pubdate#. 2 (55):#startpage. 2010

10030Pierce, E. S.. Ulcerative colitis and Crohn's disease: is Mycobacterium avium subspecies paratuberculosis the common villain?. Gut Pathog. 2010. 1 (2):21. 2010

10044

Rosenfeld, G. and Bressler, B. Mycobacterium avium paratuberculosis and the etiology of Crohn's disease: a review of the controversy from the clinician's perspective. Can J Gastroenterol. 2010. 10 (24) 2010

- Verification results: 18 potentially relevant citations not in the SR database. One we obtained to verify relevance (Van Kruiningen 2001), 6 were previously screened lit reviews and 12 were not relevant (did not look at MAP or looked at treatment therapies).


Relevance Tool for Screening Abstracts –2013 update on the zoonotic potential of M. Paratuberculosis

Ref ID_______________

Reviewer:____________

Relevance Criteria

1) Does the abstract investigate

A potential association between human disease and Mycobacterium avium subspecies Paratuberculosis (MAP) isolated from humans?

□ yes

A potential association between Johne’s Disease (MAP or Paratuberculosis) in ruminants AND human disease?

□ yes

Pasteurized dairy products or meat or water or other human food as a potential source of MAP?

□ no

NONE OF ABOVE □ no

2) Does this abstract describe primary research in English? □ yes

No: foreign language either primary or literature review □ no

No: English review article □ no

No: this is a risk assessment, economic evaluation, predictive modeling article in English etc.

□ no

No: other specify_________ □ no__

Footnotes:Please note that Mycobacterium avium subspecies paratuberculosis is also called MAP and/or Mycobacterium paratuberculosis.------------------------------------------------------------------------------------------------------------Reviewer Decision If the response to question 1 and 2 is ‘Y’ the paper should be obtained and moves to the critical appraisal phase.If the response is ‘N’ to questions 1 or 2 then the reviewer decision is ‘N’.------------------------------------------------------------------------------------------------------------

Both reviewers must agree, conflicts resolved by consensus.


GRADE Implementation:

What is GRADE?

Risk of Bias Assessment and use of GRADE

The risk of bias assessment aims to assess the internal validity of the study, ie: whether it answers the research question correctly. In this sense we are assessing systematic error, deviation from the truth, in results or inferences (7-9). These biases may vary in direction and magnitude; however it is impossible to know the extent that the biases have influenced the results of a study (7). By assessing the risk of bias we are indicating the extent to which the study results should be believed. This assessment evaluates selection bias, performance bias, attrition bias, detection bias, and reporting bias. We have also added an assessment of confounding for the observational studies. The results of this help us to use the GRADE criteria to grade the evidence (8-10).

The reason why we have moved away from “quality” is that it gets away from the issue of quality of reporting verses quality of conduct. In addition to moving away from more subjective judgements such as whether the study employed the most appropriate tools for outcome assessment.

The results of risk of bias will be summarized and if warranted we will explore the possible impact that these results have on the results of studies by conducting subgroup meta-analyses and/or meta-regression if there is enough power.

How does it Work?

Formula for implementing GRADE on this review update.

GRADE has 7 components:

1. Limitations in the design and implementation (risk of bias) (down)

2. Indirectness of Evidence (down)

3. Unexplained heterogeneity (down)

4. Imprecision of Results (down)/ Large Consistent Precise estimates (up)

5. High probability of Publication Bias (down)

6. Studies are underestimating effect (up)

7. Dose-response gradient detected (up)


GRADE Assessment of Bias

Questions with answers and explanation (replaces quality assessment from the 2005 protocol)

Note: All relevant papers, including those in the original review, were subjected to this GRADE assessment

GRD Com

Study Design Question Answers Explanation

1-1 Intervention (Ct, Cht)

Was allocation sequence adequately generated?

Yes, allocation sequence is described in sufficient detail. ___page#?

Unclear - simple statement that says they "randomized"

No

NA

Selection bias, (8.5.a)

less of an issue with agricultural animal studies.

Yes- random number table/ sequence generation, coin toss, etc.

No- non-random generation eg. Odd or even, date of admission, judgment of researcher etc.

1-2 Intervention (Ct, Cht)

Was the allocation sequence adequately concealed from the participants and the researcher?

Yes, concealment was sufficient and allocation was unlikely to be foreseen. ___page#?

Unclear- only said they "blinding or concealed treatment"

No

NA

Selection bias (8.5.a)

Less of an issue with agricultural animals

Yes, central allocation, sequentially numbered drugs etc., coding of some sort.

No, if assignment is foreseen due to alternation, date of birth, case number etc.

Unclear, methods of concealment not described.

1-3 Cohort Was the level of exposure representative of exposure in the population of interest?

Yes,

Unclear- too few details are available to make a clear Judgement.

No

NA

Selection bias (added)

Yes, Does the sample reflect the proportion of high risk and low risk people in the population the investigator would like to extrapolate the results to?

No,

1-4 Cross-sectional &

Were the study participants (samples)

Yes, Selection bias (added)


Prevalence

OR

Case Control

selected randomly so the sample reflects disease and exposure in the population of interest?

OR

Were the controls selected from the same source population as the cases?


No

NA

Yes: Random selection of the study participants or samples are stated and described.

No: Study participants were selected non-randomly or were not Described

NA

1-17 All Was blinding appropriate? (Patient, doctor, farm hand, outcome assessor, manuscript writer.) Please note if there is a different answer for different outcomes.

Yes,

Unclear, reported that blinding was used

No _explain_____

Performance and detection bias. (8.5.a)

Was knowledge of the intervention/ status of the individual or sample adequately prevented during the study?

1-5 Intervention (Ct, ChT), Cohort

Was loss to follow-up reported and equal in both groups

Yes, ___page#?___


No _explain_____

NA

Attrition Bias (8.5.a)

Yes, loss to follow-up was reported and discussed OR there was NO loss to follow-up. There is no reason to believe that the missing data is related to the outcome, balanced loss across groups, and missing data has been dealt with in the analysis.

No: there was loss to follow-up of concern (>20%), it was not clearly reported or discussed. Reason for loss is related to the study group (intervention), the as treated analysis shows there is an issue with the remaining participants.

NA - no loss to follow-up

1-6 All Were observations Yes, ___page#? Attrition bias – (8.5.a)


excluded from the analysis reported?


No _explain_____

Yes, all exclusions from analysis and a reasonable justification were reported OR there were NO exclusions. Thus there is no concern about this.

No, exclusions were made from the analysis and it is unclear why or what impact this has on the conclusions. There is concern about this biasing the study results.

1-7 All Does the study appear to have reported all intended outcomes?

Yes, ___page#?


No _explain_____

Reporting bias (8.5.a)

Selective reporting of results because they are statistically non-significant.

Yes, the author reported all outcomes identified in the methods and do not appear to have selectively not reported any.

No, the author did not report all outcomes identified in the methods. Outcomes are not reported in a way that they can be used in a meta-analysis.

1-8 All Was the study free of other problems that could put it at a high risk of bias?

Yes


No _explain_____

All other bias' that could put the study at risk. (8.5.a)

e.g.: non-randomization, clusters, stopping the study early without explanation, sample size intended (these are NOT more likely to have biased results)

Vs.

Obvious imbalance in baseline factors that have an influence on the outcome. Outcome assessment can become biased.


Selective reporting of subgroups can be biased (these ARE more likely to have biased results)

Yes, I have no additional concerns about the design and/or conduct and reporting of this study.

No, the following are concerns I have that this study is at risk of bias. (list with page#)

1-9 All Are there any concerns that confounders have not been appropriately identified and accounted?

Yes

Raw Data

No

Confounding bias (added)

Yes: All-important confounding factors were identified, accounted for by exclusion, matching or analysis (sex, age) or are taken care of in the design of the study.

Partial: some confounders controlled but not all of them.

No: Not stated.

All Was sample size justified?

Yes

Partial

No

Not a Cochrane QA criteria

Yes: Use of sample-size formulas, based on desired power or precision and estimate of expected variability to detect differences.

Partial: Informal guesses of a sample size.

No: No details in the text.

1-10 All –

Risk of Bias

Risk of Bias Assessment based on last 11 questions

Low risk of bias

Unclear Risk of Bias

High Risk of Bias

Chtp 8 & Table 8.5.a handbook

Answers to the 11 questions above will inform the result of the RoB.

Low risk of bias, no biases were indicated in the assessment. Thus plausible bias is unlikely in


all key domains (within this study). (Across studies: most studies indicate low risk)

Unclear risk of bias, there are plausible bias that raises doubt about the results as some key domains are “unclear (within this study). (Across studies: most information is from low or unclear RoB).

High Risk of bias indicates that in one or more of the domains serious plausible bias was identified (within the study). (Across studies: The proportion of studies that are at high risk of bias is sufficient to affect the interpretation of results.)

2-1 All-

Indirectness

Does this study examine the question of interest directly?

Yes, this study directly addresses the question of interest.

No, this study indirectly examines the question of interest.

A study may indirectly address the question of interest if:

e.g. interventions we wish to compare are measured independently in two separate trials compared to controls.

e.g. the population, intervention , comparisons or outcomes were not exactly what we are trying to draw conclusions for.

* Downgrading occurs if there is reason to believe that there may be differences in the conclusions due to indirectness.

3-1 All-

Heterogeneity

(May only be addressed at synthesis)

Does this study agree with other studies addressing the same question? If no, are there reasons why?

Yes, this study is in alignment with other studies addressing the same question.

No, measure of effect or association differs in magnitude (or direction) for

If there is heterogeneity present for a group of studies this should be examined for an explanation e.g. population, dose, or other identified moderators. If there is NO plausible explanation, the


the following reasons _________________

down-grading may be recommended.

4-1 All-

Imprecision

Consider the magnitude and precision of the results for upgrading or down grading?

Upgrade: large magnitude, precise results

No concern: results are precise

Downgrade: low power, imprecision, little confidence is the outcome measure.

Upgrade: large RR>2-RR<0.5 or v. large RR>5-RR<0.2, reasonably precise and no threat to validity = confident in the observation of this study.

No concern: Reasonably precise, sample size was adequate. Outcome estimate is not large enough to consider upgrading.

Downgrade: Confidence intervals are wide, they include (or almost) the null even though the measure of association is not near the null, thus there is concern about the power of this study and I have low confidence in the outcome estimate.

5-1 All –

Publication Bias

Was this study funded by industry, was there heavy sponsor involvement?

No, There are no concerns about suppression of studies.

Yes, There was sponsor involvement.

This criteria for down-grading would be used if all or most of the trials captured are industry funded or declare heavy sponsor involvement, in which case there are concerns that studies of null or negative effect may have been suppressed from publication.

(Selective outcome reporting is covered under criteria #1.)

6-1 All –

Underestimation of Effect

Is there reason to believe that due to the population studied, the magnitude of effect (association) of the intervention (outcome) may be underestimated?

Yes, an underestimation is likely

No, there is no reason to believe the estimated effect is underestimated.

You would answer yes ONLY if there was good reason to think that the study underestimated the potential association or effect of an intervention due to the population that was sampled.

E.g. a drug was only tested on


severely disease individuals and not on all diseased individuals, but it is likely that a better success rate would have been found if all diseased individuals were studied.

e.g. The magnitude of association was lower than it likely is in the general population because the comparison group has a similar disease which in also more likely to result in having the exposure of interest.

7-1 All-

Dose-response

Was a dose-response gradient detected for the intervention or exposure being examined?

Yes, dose-response gradient detected.

No, no does-response gradient reported.

If a dose response gradient is demonstrated in some or all of the studies, this increases our confidence in the findings of the study and thus we can consider upgrading the evidence.


Data Extraction

Please note that the DE forms used in this update were the same as those from the 2005 update with the addition of GRADE. Please refer to the original protocol for the forms.

References:

1. Procite for windows 5.0 [Reference manager]. ISI ResearchSoft Inc.Version 5.0.3. ISI ResearchSoft Inc.; 1995; c1995-2003.

2. SRS 3.0 [Electronic Systematic Review]. O'Blenis P., software development management. VP Product Management. Version 3.0. Ottawa, ON: TrialStat Corporation; 2004 Oct 1; c2001-2004. 44 ByWard Market Square, Suite 270, Ottawa, ON, Canada, K1N 7A2.

3. Vi Nguyen, Lisa Waddell, Janet Harris, Ashley Baynton and Andrijana Rajić. The Evaluation of Search Strategies for Three Systematic Reviews in Zoonotic Public Health. 2008. Internal report. Public Health Agency of Canada.

4. Feller M, Huwiler K, Stephan R, Altpeter E, Shang A, Furrer H, Pfyffer GE, Jemmi T, Baumgartner A, Egger M. Mycobacterium avium subspecies paratuberculosis and crohn's disease: A systematic review and meta-analysis. Lancet Infect Dis [Internet]. 2007 09;7(9):607-13.

5. Abubakar I, Myhill D, Aliyu SH, Hunter PR. Detection of mycobacterium avium subspecies paratuberculosis from patients with crohn's disease using nucleic acid-based techniques: A systematic review and meta-analysis. Inflamm Bowel Dis [Internet]. 2008 03;14(3):401-10.

6. Eltholth MM, Marsh VR, Van Winden S, Guitian FJ. Contamination of food products with mycobacterium avium paratuberculosis: A systematic review. J Appl Microbiol [Internet]. 2009 10;107(4):1061-71.

7. Higgins J, Altman D. Chapter 8: Assessing risk of bias in included studies.In: In: Higgins JPT,Green S editors, editor. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (updated September 2008). [Internet]. The Cochrane Collaboration; 2008

8. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH. GRADE guidelines: 3. rating the quality of evidence. J Clin Epidemiol [Internet]. 2011 04;64(4):401-6.

9. Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: A new series of articles in the journal of clinical epidemiology. J Clin Epidemiol [Internet]. 2011 04;64(4):380-2.

10. Schunemann H, Hill S, Guyatt G, Akl EA, Ahmed F. The GRADE approach and bradford hill's criteria for causation. J Epidemiol Community Health [Internet]. 2010 10/14


Summary of risk of bias and study level GRADE components by study-outcome for included in the zoonotic potential of M. paratuberculosis SR-MA.

REFID Author Year GRADE 1-4

GRADE 1-6

GRADE 1-7

GRADE4-1

GRADE 6-1

GRADE 7-1

GRADE 8-1

GRADE 1-9

GRADE 1-10

GRADE 2-1

GRADE 5-1

Lab method Data

yes UnclearNoNA

YES,unclearNo

YESunclearNo

Yes No.

YesNo

YesUnclearNo

YesRaw dataNo

Low unclearhigh

YesNo

NoYes

Culture-PCRPCRCultureELISAImmuno. Hybridiz.Staining

Dis.n

Dis. pos

CONn

CONpos

30 Tuci 2011 Unclear No Yes no grade change No No Yes No unclear Yes No PCR 31 21 43 24

70 Imirzalioglu 2011 Yes No Yes no grade change No No Yes yes Low Yes No PCR 6 2 1287 25

170 Campos 2011 Unclear No Yes down grade No No Yes No unclear no No ELISA

190 Biet 2011 Unclear No Yes down grade No No Yes No unclear no No ELISA 81 27 191 29

220 Bach 2011 No No Yes down grade No No yes No low No No ELISA

510 Shin 2010 No no Yes down grade No No Yes yes high No No ELISA

520 Sibartie 2010 unclear Yes Yes down grade No yes Yes No unclear no No Immuno

550 Sasikala 2010 Yes No Yes down grade No No Yes No low Yes No PCR 81 0 85 0

800 Olsen 2009 Yes no Yes down grade No No Yes No low no No Immuno 7 5 18 3

860 Parrish 2009 unclear No Yes down grade No No Yes Yes Unclear Yes No PCR 130 0 130 1

1210 Bentley 2008 yes no Yes no grade change No No unclear Yes unclear Yes no PCR 361 122 200 43

1230 Chamberlin 2008 ND Unclear Unclear down grade Unclear No No No Unclear Yes Unclear culture 19 9 8 0

10017 Magin 2013 unclear no yes down grade no no unclear unclear unclear no no immuno 28 0 17 0

10019 Molicotti 2013 unclear no yes no grade change no no yes yes unclear yes no PCR 12 8 11 1

10029 Verdier 2013 ND no yes down grade no no yes no low no no ELISA

10053 Elguezabal 2012 unclear no yes no grade change no no yes no unclear yes no PCR 173 37 293 105

10114 Singh 2011 unclear no yes down grade no no yes no unclear no no ELISA 5 4 35 3

10113a Singh 2011 unclear no yes down grade no no unclear yes. high yes no staining 58 16 40 0

10113b Singh 2011 unclear no yes down grade no no unclear yes high yes no culture 58 29 40 5


10113c Singh 2011 unclear no yes down grade no no unclear Yes* high yes no PCR 29 24 5 410557 SV Polymeros 2006 Unclear No Yes down grade No No Yes No low No No ELISA 50 15 88 5

12-2005 Dell'Isola 1994 Yes no yes no grade change no no yes No low yes no PCR 18 13 35 9

1260a Singh 2008 no No Unclear down grade No No Yes yes unclear no no ELISA 6 5 72 27

1260b Singh 2008 no No Unclear down grade No No Yes yes unclear no no ELISA 6 2 72 29

1260c Singh 2008 no No Unclear no grade change No No Yes yes unclear Yes no culture-PCR 5 4 30 10

12828 SV Netea 2006 Unclear Unclear Unclear down grade Unclear No Unclear Unclear Unclear No No immuno

1300a Ren 2008 unclear No Yes down grade Unclear No Yes No unclear no No ELISA

1300b Ren 2008 unclear No Yes no grade change Unclear No Yes No unclear Yes No PCR 46 12 70 9141a-2005 Naser 2004 No no yes no grade change no no yes No unclear yes no PCR 28 13 24 7

141b-2005 Naser 2004 No no yes no grade change no no yes No unclear yes no culture 28 14 24 2

14-2005 Elsaghier 1992 Yes no yes down grade no no yes Yes low no no ELISA 29 16 38 2

150a Lee 2011 Yes NO Yes down grade No No Yes No low no No ELISA

150b Lee 2011 Yes NO Yes no grade change No No Yes No low Yes No PCR 20 7 39 2

150c Lee 2011 Yes NO Yes no grade change No No Yes No low Yes No PCR 9 5 38 1162a-2005 Sechi 2004 Yes no yes no grade change no no yes Yes low yes no Hybridiz. 82 73 40 0

162b-2005 Sechi 2004 Yes no yes no grade change no no yes Yes low yes no PCR 82 11 40 0

172-2005 Bernstein 2003 Yes no yes no grade change no no yes No low yes no PCR 24 0 56 7

20 a Di Sabatino 2011 Unclear No Yes down grade No No Yes No Unclear no No ELISA 70 4 130 9

20 b Di Sabatino 2011 Unclear No Yes down grade No No Yes No Unclear no No ELISA 70 5 130 8

20 c Di Sabatino 2011 Unclear No Yes down grade No No Yes No Unclear no No ELISA 70 2 130 2

20 d Di Sabatino 2011 Unclear No Yes no grade change No No Yes No Unclear Yes No PCR 70 48 130 26205-2005 Ryan 2002 Yes no yes no grade change no no yes Yes low yes no PCR 15 6 12 0

2255-2005 Cohavy 1999 Yes no yes down grade no no yes Yes low no no immuno 10 9 20 0

234a-2005 Collins 2000 No no yes down grade no no yes Yes unclear no no immuno 261 30 487 21

234b-2005 Collins 2000 No no yes down grade no no yes Yes unclear no no immuno 261 _ 487 0

234c-2005 Collins 2000 No no yes down grade no no yes Yes unclear yes no culture 83 0 110 0

234d- Collins 2000 No no yes no grade change no no yes Yes unclear yes no PCR 79 15 99 19


20052417-2005 Kobayashi 1988 Yes no yes down grade no no yes No low no yes ELISA 72 0 137 0

25-2005 Kanazawa 1999 Yes no yes down grade no no yes No low yes no PCR 13 0 27 0272a-2005 Hulten 2001 Yes no yes no grade change no no yes No low yes no PCR 37 9 43 3

272b-2005 Hulten 2001 Yes no yes no grade change no no yes No low yes no Hybridiz. 37 7 43 2

279a-2005 Olsen 2001 Yes no yes down grade no no yes No low no no ELISA 10 6 10 1

279b-2005 Olsen 2001 Yes no yes down grade no No low no no immuno 10 _ 10 0

280a Ricanek 2010 Yes No Yes no grade change No No Yes No Low Yes No culture 75 2 215 2

280b Ricanek 2010 Yes No Yes no grade change No No Yes No Low Yes No culture 7 7 26 10

280c Ricanek 2010 Yes No Yes no grade change No No Yes No Low Yes No culture-PCR 75 0 215 1

280d Ricanek 2010 Yes No Yes no grade change No No Yes No Low Yes No culture-PCR 7 2 26 1

28-2005 Matthews 1980 Yes yes no down grade no no unclear Yes high no no immuno 24 17 48 36282-2005 Gibson 2000 No no yes down grade no no yes Yes Low yes no PCR 3 0 21 0

2862-2005 Autschbach 2005 Yes no yes no grade change no no yes No Low yes no PCR 100 52 200 7

288-2005 Naser 2000 Yes no yes no grade change no no yes No Low no no Immuno 53 39 45 1

2945a-2005 Sechi 2005 Yes no yes no grade change no no yes No Low yes no PCR 30 25 31 3

2945b-2005 Sechi 2005 Yes no yes no grade change no no yes No Low yes no culture 30 19 31 3

314-2005 Murray 1995 Yes no yes no grade change no no yes No Low yes no PCR 9 2 30 2

320a Mendoza 2010 Unclear No Yes no grade change No No Yes No Low Yes No culture-PCR 30 30 39 39

320b Mendoza 2010 Unclear No Yes no grade change No No Yes No Low Yes No culture-PCR 30 0 39 1

320c Mendoza 2010 Unclear No Yes no grade change No No Yes No Low Yes No PCR 30 30 39 39329-2005 El-Zaatari 1999 Yes no yes down grade no no yes No Low no no immuno 89 77 110 35

332-2005 Suenaga 1999 No no yes down grade no no yes Yes unclear no no immuno 13 5 44 6

353-2005 Fujita 2002 Yes no yes down grade no no yes No Low yes no PCR 16 0 29 0

363a-2005 Kallinowski 1998 Yes no yes down grade no no yes No Low no no immuno 19 0 34 0

363b- Kallinowski 1998 Yes no yes down grade no no yes No Low yes no PCR 19 0 34 0


2005373-2005 Chiba 1998 Yes no yes down grade no no yes Yes Low yes no PCR 30 0 14 0

397-2005 Al-Sharmale 1997 Yes no yes down grade no no yes No Low yes no PCR 10 0 27 0

40 a Rath 2011 Unclear No Yes down grade No No No Unclear unclear Yes No Culture 10 0 32 0

40 b Rath 2011 Unclear No Yes no grade change No No No Unclear. unclear Yes No culture-PCR 14 1 70 17

40-2005 Schwartz 2000 Yes no yes no grade change no no no Yes Low yes no culture-PCR 27 10 36 2

408-2005 Mishina 1996 Yes no yes down grade no no yes Yes Low yes no PCR 8 8 4 2

414-2005 Walmsley 1996 No yes no down grade no no yes Yes Low no no immuno 40 56 0

418-2005 Dumonceau 1996 Yes no yes down grade no no yes No Low yes no PCR 36 0 36 0

428-2005 Frank 1996 Yes no yes down grade (no

MAP) no no yes Yes Low yes no PCR 23 0 11 0

430-2005

Kreuzpaintner 1995 Yes no yes no grade change no no yes No Low yes no culture 23 12 23 0

435-2005 Rowbotham 1995 No no yes down grade no no yes No Low no no Immuno 13 34 0

441-2005 Rowbotham 1995 Yes no yes no grade change no no yes No Low yes no PCR 68 0 75 1

44-2005 Suenaga 1995 Yes yes yes no grade change no no yes No Low yes no PCR 10 10 34 25450-2005 Bernstein 2004 Yes no yes down grade no no yes No Low no no ELISA 283 107 684 232

461-2005 Lisby 1994 Yes no yes no grade change no no yes No Low yes no PCR 82 15 110 5

474-2005 Fidler 1994 Yes no yes no grade change no no yes No Low yes no PCR 31 4 30 0

477-2005 Vannuffel 1994 No no yes down grade no no yes No Low no no immuno 73 26 50 0

495-2005 Wall 1993 Yes no yes no grade change no no yes Yes Low yes no PCR 17 6 5 0

508-2005 Stainsby 1993 No yes no down grade no no yes Yes unclear no no ELISA 53 8 44 2

519-2005 McFadden 1992 Yes no yes no grade change no no yes Yes low RoB yes no culture-

PCR 27 1 55 0

523-2005 Moss 1992 No no yes no grade change no no yes Yes unclear yes no PCR 18 6 11 1

524-2005 Sanderson 1992 Yes no yes no grade change no no yes Yes Low yes no PCR 40 26 63 6

539-2005 Ebert 1991 Yes no yes down grade no no yes No Low no no immuno

544-2005 Tanaka 1991 yes yes no down grade no no yes no Low no no immuno 18 0 10 0


55-2005 Romero 2005 Yes no yes no grade change no no yes No Low yes no Hybridiz. 12 8 8 0

55-2005 Romero 2005 Yes no yes no grade change no no yes No Low yes no PCR 12 10 8 3581-2005 Butcher 1988 Yes no yes down grade no no yes Yes Low yes no Hybridiz. 17 0 4 0

593-2005 Graham 1987 Yes no yes down grade no no yes Yes Low yes no culture 59 0 46 0

595-2005 Yoshimura 1987 Yes no yes no grade change no no yes Yes Low yes no Hybridiz. 19 10 12 3

610a Kirkwood 2009 Yes No Yes no grade change No No Yes No Low Yes No culture-PCR 10 4 6 0

610b Kirkwood 2009 Yes No Yes no grade change No No Yes No Low Yes No PCR 56 22 61 13

610c Kirkwood 2009 Yes No Yes no grade change No No Yes No Low Yes No PCR 50 8 56 2630a-2005 Del Prete 1998 Yes no yes no grade change no no yes No Low yes no PCR 32 15 68 10

630b-2005 Del Prete 1998 Yes no yes no grade change no no yes No Low yes no culture-

PCR 32 8 68 6

654a-2005 Clarkston 1998 Yes no yes down grade no no yes No Low yes no culture 21 0 16 0

654b-2005 Clarkston 1998 Yes no yes no grade change no no yes No Low yes no PCR 21 1 16 0

67-2005 Ellingson 2003 Yes no yes down grade no no yes Yes Low yes no PCR 35 0 57 0

6a- 2005 Bull 2003 Yes no yes no grade change no no yes No Low yes no PCR 37 34 34 9

6b-2005 Bull 2003 Yes no yes no grade change no no yes No Low yes no culture-PCR 33 14 33 3

89-2005 Cellier 1998 Yes no yes down grade no no yes No Low yes no PCR 47 0 47 0

910a Juste 2009 Unclear No Yes down grade No No Yes Unclear Unclear no No ELISA

910b Juste 2009 Unclear No Yes no grade change No No Yes Unclear Unclear Yes No PCR 124 19 178 5313356 SV Naser 1999 no no yes downgrade no no no yes high yes No culture-

PCR 26 15 5 23

10831 SV Eishi 2002 yes No yes down grade No No Yes unclear Low Yes No PCR 108 0 151

10944a SV El-Zaatari 1996 yes No Yes down grade No No unclear unclear unclear no No Immuno 7 7 50 5

10944b SV El-Zaatari 1996 yes No Yes down grade No No unclear unclear unclear no No Immuno 6 5 38 5

10003 Bitti 2012 unclear no yes down grade no no yes no low no no ELISA 247 76 110 0

10003 Bitti 2012 Unclear no yes no grade change no no yes no unclear yes no PCR 247 30 110 4

10006 Cossu 2013 Unclear no yes down grade no no yes no unclear yes no ELISA 3

10082 Masala 2012 unclear no yes down grade no no yes no unclear yes no ELISA 50 22 51

10086a Naser 2013 unclear no yes down grade no no yes no unclear no no ELISA 10 5 8 18

10086b Naser 2013 unclear no yes no grade change no no yes no unclear yes no culture- 10 3 8


PCR10176 SV Paccagnini 2009 Unclear No Yes no grade change No No Unclear Yes unclear Yes No PCR 59 33 79

10007 Cossu 2011 unclear no yes down grade no no unclear yes unclear no no ELISA 1010245 cSV Rosu 2009 unclear No YES down grade No No unclear Yes unclear no No ELISA 57 33 79 2

10245a SV Rosu 2009 unclear No YES down grade No No unclear Yes unclear no No ELISA 57 27 79 6

10245b SV Rosu 2009 unclear No YES down grade No No unclear Yes unclear no No ELISA 57 17 79 12

10245d SV Rosu 2009 unclear No YES down grade No No unclear Yes unclear no No ELISA 57 40 79

10245d SV Rosu 2009 unclear No YES down grade No No unclear Yes unclear no No ELISA 57 26 79 0

10245e SV Rosu 2009 unclear No YES no grade change No No unclear Yes unclear yes No culture-

PCR 10 2 10 0

10348 SV Rosu 2008 unclear No Yes down grade No No unclear Yes unclear No No ELISA #REF!

10000-2013 Sisto M 2010 NA no yes no grade change No No yes NO low yes no PCR-nested 1 1 2 2

10001-2013 D'Amore M 2010 NA no yes no grade change No No yes NO low yes no PCR-nested

10005-2013 Frau 2013 no no yes Down grade no no yes no unclear yes no PCR 435 68 264 6

10005-2013 Frau 2013 no no yes Down grade no no yes no unclear yes no ELISA 435 123 264 10

10007-2013 Cossu 2013 no no yes Down grade no no yes no unclear yes no ELISA 268 62 231 15

585-2005 McFadden 1988 No yes no down grade no no yes Yes unclear no no immuno 20 1 2

153-2005 Nakase 2006 no no yes down grade no no yes no unclear ELISA 50 24 104 0

153-2005 Nakase 2006 no no yes down grade no no yes no unclear ELISA 50 22 104

153-2005 Nakase 2006 no no yes down grade no no yes no unclear ELISA 50 0

61-2008 Bernstein 2007 yes ND yes Down grade no no yes yes low no no ELISA236-2008 Bibiloni 2006 yes no yes Down grade no no yes raw

data low yes no PCR 20 0

259-2008 Cheng 2005 yes ND yes no grade change no no yes raw

data low yes no PCR 9 13

58-2008 Clancy 2007 yes ND yes no grade change no no yes no low yes no PCR 63 15 0

58-2008 Clancy 2007 yes ND yes downgrade no no yes no low no no ELISA 18

66-2008 Lozano-Leon 2006 yes ND yes downgrade no no yes yes low yes no PCR 73 0 75

35-2008 Scanu 2007 yes ND yes no grade change no no yes raw low yes no PCR 23 20 40 7


data64-2008 Sechi 2006 yes ND yes no grade change no no yes no low yes no PCR122-2008 Sechi 2005 yes ND yes no grade change no no yes no low yes no PCR 37 25 34

541-2005 Naser 2000 no no yes no grade change no no yes no unclear yes no culture 2 2 5 0

10008-2013 Pistone 2012 yes ND yes no grade change no no yes no low yes no PCR 35 23 53 13

3030 Singh 2009 No No Yes no grade change No NA Unclear Yes unclear yes no

210 Wagner 2011 Unclear no yes no grade change no NA yes raw data low yes no

2969 Jones 2006 Unclear no yes no grade change no yes raw data low no no

410 Qual 2010 Yes No Yes No grade change No Yes No low yes No 2495-2005

VanKruiningen 1986 no no yes down grade no no no no unclear yes no

559-2005 Gitnick 1989 no no yes down grade no no no no unclear yes no

10128 Wynne, 2011 no no yes no grade change no no yes no low yes no301- 2005 Whittington 2000 no no yes no grade change no no yes no low yes no

98- 2005 Ghadiali 2004 no no yes no grade change no no yes no low yes no190- 2005 Motiwala 2003 no no yes no grade change no no yes no low yes no

402- 2005 Francois 1997 no no yes no grade change no no yes no low yes no

2650 Singh 2010 Unclear no Yes no grade change No No Yes yes unclear yes No

REFID: is a unique identifier used in the SR and can be cross-referenced with the included studies list.GRADE questions and answer description can be found in the study assessment form in the preceding section of this supplementary material.ND – not discussed, NA- not applicable, hybridiz. – Hybridization methods used to isolate M. paratuberculosis. Immuno- indicates immunology methods other than ELISA (e.g. cytokine activity) were used to evaluate a possible association. Data: Dis n and Dis. Pos is the total number and number testing positive in the diseased group, this is mainly Crohn’s disease patients, but the studies on other diseases are also included in this table. Con n and Con pos is the total number and number testing positive in the control group.


Documents

Appendix - List of Relevant studies included and excluded ...cambridge.org:id:... · Web viewClancy R, Ren Z, Turton J, Pang G, Wettstein A. Molecular evidence for mycobacterium