Helicobacter Pylori is the Cause of Human Gastric Cancer
Main Article Content
Abstract
Background—Helicobacter pylori (HP) infection has been repeatedly reported to be associated with human gastric cancer (GC). However, Epstein Bar virus (EBV) has been found in gastric cancer tissues too. It is therefore not surprising that it proved difficult to establish a causal relationship between Helicobacter pylori and gastric cancer. A systematic review and meta-analysis of observational studies was performed to re-investigate the relationship between Helicobacter pylori and gastric cancer.
Material and methods—The electronic database PubMed was searched for titles and abstracts of studies which investigated the relationship between HP and GC. Four eligible Japanese studies were included in this meta-analysis (196 incident gastric cancers among a total of 14792 individuals). The data available were analysed by new statistical methods. This study considers 5% as a reasonable cut-off for statistical significance.
Results—The studies reviewed provided highly significant evidence that a HP infection is a necessary condition of GC. In everyday language, without a helicobacter pylori infection, no human gastric cancer (P Value < .004). In the same respect, the causal relationship between HP and GC was highly significant too.
Conclusion—In a systematic review and meta-analysis, it was possible to establish a causal relationship between HP and GC. Helicobacter pylori is the cause of human gastric cancer.
Keywords:
Helicobacter pylori, human gastric cancer, cause effect relationship
Article Details
How to Cite
BARUKČIĆ, Ilija.
Helicobacter Pylori is the Cause of Human Gastric Cancer.
Medical Research Archives, [S.l.], v. 11, n. 2, feb. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3555>. Date accessed: 23 nov. 2024.
doi: https://doi.org/10.18103/mra.v11i2.3555.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Montano V, Didelot X, Foll M, et al. Worldwide Population Structure, Long-Term Demography, and Local Adaptation of Helicobacter pylori. Genetics. 2015;200(3):947-963. doi:10.1534/genetics.115.176404
2. Moodley Y, Linz B, Bond RP, et al. Age of the association between Helicobacter pylori and man. PLoS Pathog. 2012;8(5):e1002693. doi:10.1371/journal.ppat.1002693
3. Yamaoka Y. Helicobacter pylori typing as a tool for tracking human migration. Clin Microbiol Infect. 2009;15(9):829-834. doi:10.1111/j.1469-0691.2009.02967.x
4. Maixner F, Krause-Kyora B, Turaev D, et al. The 5300-year-old Helicobacter pylori genome of the Iceman. Science. 2016;351(6269):162-165. doi:10.1126/science.aad2545
5. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1(8390):1311-1315. doi:10.1016/s0140-6736(84)91816-6
6. Hooi JKY, Lai WY, Ng WK, et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology. 2017;153(2):420-429. doi:10.1053/j.gastro.2017.04.022
7. Coelho LGV, Marinho JR, Genta R, et al. IV th brazilian consensus conference on helicobacter pylori infection. Arq Gastroenterol. 2018;55(2):97-121. doi:10.1590/S0004-2803.201800000-20
8. Sjomina O, Pavlova J, Niv Y, Leja M. Epidemiology of Helicobacter pylori infection. Helicobacter. 2018;23 Suppl 1:e12514. doi:10.1111/hel.12514
9. Sgambato D, Visciola G, Ferrante E, et al. Prevalence of Helicobacter pylori infection in sexual partners of H. pylori-infected subjects: Role of gastroesophageal reflux. United European Gastroenterol J. 2018;6(10):1470-1476. doi:10.1177/2050640618800628
10. Mladenova I, Durazzo M. Transmission of Helicobacter pylori. Minerva Gastroenterol Dietol. 2018;64(3):251-254. doi:10.23736/S1121-421X.18.02480-7
11. Ata AA, Kamel IA. Primary reticulum cell sarcoma of the liver. A case report. J Egypt Med Assoc. 1965;48(7):514-521.
12. Violeta Filip P, Cuciureanu D, Sorina Diaconu L, Maria Vladareanu A, Silvia Pop C. MALT lymphoma: epidemiology, clinical diagnosis and treatment. J Med Life. 2018;11(3):187-193. doi:10.25122/jml-2018-0035
13. Barukčić I. Helicobacter pylori—The Cause of Human Gastric Cancer. Journal of Biosciences and Medicines. 2017;5(2):1-9. doi:10.4236/jbm.2017.52001
14. Barukčić I. Helicobacter Pylori is the Cause of Gastric Cancer. Modern Health Science. 2018;1(1):43-50. doi:10.30560/mhs.v1n1p43
15. IARC. Schistosomes, liver flukes and Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241.
16. Rokkas T, Rokka A, Portincasa P. A systematic review and meta-analysis of the role of Helicobacter pylori eradication in preventing gastric cancer. Ann Gastroenterol. 2017;30(4):414-423. doi:10.20524/aog.2017.0144
17. Ford AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut. 2020;69(12):2113-2121. doi:10.1136/gutjnl-2020-320839
18. Epstein MA, Achong BG, Barr YM. Virus Particles in Cultured Lymphoblasts from Burkitt’s Lymphoma. Lancet. 1964;283(7335):702-703. doi:https://doi.org/10.1016/S0140-6736(64)91524-7
19. Kume T, Oshima K, Shinohara T, et al. Low rate of apoptosis and overexpression of bcl-2 in Epstein-Barr virus-associated gastric carcinoma. Histopathology. 1999;34(6):502-509. doi:10.1111/j.1365-2559.1999.00686.x
20. Chen XZ, Chen H, Castro FA, Hu JK, Brenner H. Epstein-Barr virus infection and gastric cancer: a systematic review. Medicine (Baltimore). 2015;94(20):e792. doi:10.1097/MD.0000000000000792
21. Dombre C, Guyot N, Moreau T, et al. Egg serpins: The chicken and/or the egg dilemma. Semin Cell Dev Biol. 2017;62:120-132. doi:10.1016/j.semcdb.2016.08.019
22. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med. 2009;3(3):e123-130.
23. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. doi:10.1371/journal.pmed.1000100
24. Ishaq S, Nunn L. Helicobacter pylori and gastric cancer: a state of the art review. Gastroenterol Hepatol Bed Bench. 2015;8(Suppl 1):S6-S14.
25. Eslick GD. Helicobacter pylori infection causes gastric cancer? A review of the epidemiological, meta-analytic, and experimental evidence. World J Gastroenterol. 2006;12(19):2991-2999. doi:10.3748/wjg.v12.i19.2991
26. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784-789. doi:10.1056/NEJMoa001999
27. Miki K. Gastric cancer screening by combined assay for serum anti-Helicobacter pylori IgG antibody and serum pepsinogen levels - “ABC method.” Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(7):405-414. doi:10.2183/pjab.87.405
28. Yoshida T, Kato J, Inoue I, et al. Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer. Int J Cancer. 2014;134(6):1445-1457. doi:10.1002/ijc.28470
29. Shuto M, Fujioka T, Matsunari O, et al. Association between Gastric Cancer Risk and Serum Helicobacter pylori Antibody Titers. Gastroenterol Res Pract. 2017;2017:1286198. doi:10.1155/2017/1286198
30. Barukčić I. The Mathematical Formula of the Causal Relationship k. IJAPM. 2016;6(2):45-65. doi:10.17706/ijapm.2016.6.2.45-65
31. Barukčić I. Die Kausalität. 1. Aufl. Wiss.-Verl; 1989.
32. Barukčić I. Die Kausalität. 2., völlig überarb. Aufl. Scientia; 1997.
33. Barukčić I. Theoriae Causalitatis Principia Mathematica. Second edition. Books on Demand GmbH; 2021.
34. Barukčić I. Causal relationship k. International Journal of Mathematics Trends and Technology IJMTT. 2020;66(10):76-115.
35. Barukčić I. The causal relationship k. MATEC Web Conf. 2021;336(2):09032. doi:10.1051/matecconf/202133609032
36. Uspensky JV. Introduction to Mathematical Probability. 1st Edition. McGraw-Hill; 1937.
37. Tschébychef PL. Des valeurs moyennes. Journal de Mathématiques Pures et Appliquées. 1867;12(2):177-184. doi:http://sites.mathdoc.fr/JMPA/PDF/JMPA_1867_2_12_A11_0.pdf
38. Barukčić I. Conditio Sine qua Non. Zenodo; 2022. doi:10.5281/zenodo.5854744
39. Spendel G. Die Kausalitätsformel Der Bedingungstheorie Für Die Handlungsdelikte: Eine Kritische Untersuchung Der Conditio-Sine-qua-Non-Formel Im Strafrecht. Univ. Diss.; 1948.
40. Barukčić I. Conditio per quam. Causation. 2022;17(3):5-86. doi:10.5281/zenodo.6369831
41. Barukčić I. Mutually exclusive events. Causation. 2021;16(11):5-57. doi:10.5281/zenodo.5746415
42. Barukčić I. Cytomegalovirus and lung cancer - a causal relationship? Causation. 2023;18(11):5-30. doi:https://doi.org/10.5281/zenodo.7548139
43. Helmert FR. Ueber die Wahrscheinlichkeit der Potenzsummen der Beobachtungsfehler und über einige damit im Zusammenhange stehende Fragen. Zeitschrift für Mathematik und Physik. 1876;21(3):102-219.
44. Pearson K. X. On the criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be reasonably supposed to have arisen from random sampling. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science. 1900;50(302):157-175.
45. Yates F. Contingency Tables Involving Small Numbers and the χ 2 Test. The Journal of the Royal Statistical Society (Supplement). 1934;1(2):217. doi:10.2307/2983604
46. Barukčić I. The P Value of likely extreme events. International Journal of Current Science Research. 2019;5(11):1841-1861.
47. Cornfield J. A method of estimating comparative rates from clinical data; applications to cancer of the lung, breast, and cervix. Journal of the National Cancer Institute. 1951;11(6):1269-1275.
48. Sadowsky DA, Gilliam AG, Cornfield J. The statistical association between smoking and carcinoma of the lung. J Natl Cancer Inst. 1953;13(5):1237-1258.
49. Barukčić I. The logical content of the risk ratio. Causation. 2021;16(4):5-41. doi:10.5281/zenodo.4679509
50. Yule GU. On the Association of Attributes in Statistics: With Illustrations from the Material of the Childhood Society, &c. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. 1900;194(252-261):257-319. doi:10.1098/rsta.1900.0019
51. Fisher RA. The Logic of Inductive Inference. Journal of the Royal Statistical Society. 1935;98(1):39-82. doi:10.2307/2342435
52. Cox DR. The Regression Analysis of Binary Sequences. Journal of the Royal Statistical Society Series B (Methodological). 1958;20(2):215-242.
53. Yule GU. On the Methods of Measuring Association Between Two Attributes. Journal of the Royal Statistical Society. 1912;75(6):579. doi:10.2307/2340126
54. Barukčić I. Index of relationship. Causation. 2021;16(8):5-37. doi:10.5281/zenodo.5163179
55. Barukčić I. Index of Unfairness. Modern Health Science. 2019;2(1):22-59. doi:10.30560/mhs.v2n1p22
56. Barukčić I. Conditions and study design. Causation. 2022;18(1):5-99. doi:10.5281/zenodo.6816088
57. Barukčić I. Causal Inference and Study Design. Zenodo; 2022. doi:10.5281/zenodo.6299686
58. Pearson K. XV. On certain properties of the hypergeometrical series, and on the fitting of such series to observation polygons in the theory of chance. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science. 1899;47(285):236-246. doi:10.1080/14786449908621253
59. Gonin HT. XIV. The use of factorial moments in the treatment of the hypergeometric distribution and in tests for regression. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science. 1936;21(139):215-226. doi:10.1080/14786443608561573
60. Pólya G. Über den zentralen Grenzwertsatz der Wahrscheinlichkeitsrechnung und das Momentenproblem: [In English: On the central limit theorem of probability calculation and the problem of moments]. Mathematische Zeitschrift. 1920;8(3-4):171-181. doi:10.1007/BF01206525
61. Barukčić I. Theoriae Causalitatis Principia Mathematica. First edition. Books on Demand GmbH; 2017.
62. Barukčić I. Unified Field Theory. Journal of Applied Mathematics and Physics. 2016;4(8):1379-1438. doi:10.4236/jamp.2016.48147
63. Barukčić I. Index of Independence. Modern Health Science. 2019;2(2):1-25. doi:10.30560/mhs.v2n2p1
64. Bergh D. Chi-Squared Test of Fit and Sample Size-A Comparison between a Random Sample Approach and a Chi-Square Value Adjustment Method. Journal of Applied Measurement. 2015;16(2):204-217.
65. Bonferroni CE. Teoria statistica delle classi e calcolo delle probabilità. Seeber; 1936.
66. Takada K. Epstein-Barr virus and gastric carcinoma. Mol Pathol. 2000;53(5):255-261. doi:10.1136/mp.53.5.255
67. Gall JG, Pardue ML. Formation and detection of RNA-DNA hybrid molecules in cytological preparations. Proceedings of the National Academy of Sciences of the United States of America. 1969;63(2):378-383. doi:10.1073/pnas.63.2.378
68. Jensen E. Technical review: In situ hybridization. Anat Rec (Hoboken). 2014;297(8):1349-1353. doi:10.1002/ar.22944
69. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953;171(4356):737-738. doi:10.1038/171737a0
70. Walker PJ, Siddell SG, Lefkowitz EJ, et al. Changes to virus taxonomy and to the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2021). Arch Virol. 2021;166(9):2633-2648. doi:10.1007/s00705-021-05156-1
71. Feederle R, Klinke O, Kutikhin A, Poirey R, Tsai MH, Delecluse HJ. Epstein-Barr Virus: From the Detection of Sequence Polymorphisms to the Recognition of Viral Types. Curr Top Microbiol Immunol. 2015;390(Pt 1):119-148. doi:10.1007/978-3-319-22822-8_7
72. Babcock GJ, Decker LL, Volk M, Thorley-Lawson DA. EBV persistence in memory B cells in vivo. Immunity. 1998;9(3):395-404.
73. Miyashita EM, Yang B, Babcock GJ, Thorley-Lawson DA. Identification of the site of Epstein-Barr virus persistence in vivo as a resting B cell. J Virol. 1997;71(7):4882-4891. doi:10.1128/JVI.71.7.4882-4891.1997
74. Amon W, Farrell PJ. Reactivation of Epstein-Barr virus from latency. Rev Med Virol. 2005;15(3):149-156. doi:10.1002/rmv.456
75. Cui J, Yan W, Xu S, et al. Anti-Epstein-Barr virus antibodies in Beijing during 2013-2017: What we have found in the different patients. PLoS One. 2018;13(3):e0193171. doi:10.1371/journal.pone.0193171
76. Garaud S, Buisseret L, Solinas C, et al. Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight. 2019;5(18):e129641, 129641. doi:10.1172/jci.insight.129641
77. David H. Rudolf Virchow and modern aspects of tumor pathology. Pathol Res Pract. 1988;183(3):356-364. doi:10.1016/S0344-0338(88)80138-9
78. Whitford P, Mallon EA, George WD, Campbell AM. Flow cytometric analysis of tumour infiltrating lymphocytes in breast cancer. Br J Cancer. 1990;62(6):971-975. doi:10.1038/bjc.1990.419
79. Barukčić I. Gastric Cancer and Epstein-Barr Virus Infection. Modern Health Science. 2018;1(2):1-18. doi:10.30560/mhs.v1n2p1
80. Peek RM, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol. 2006;208(2):233-248. doi:10.1002/path.1868
81. Peek RM, Fiske C, Wilson KT. Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiol Rev. 2010;90(3):831-858. doi:10.1152/physrev.00039.2009
82. Wong BCY, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004;291(2):187-194. doi:10.1001/jama.291.2.187
83. Chiang TH, Chang WJ, Chen SLS, et al. Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands. Gut. 2021;70(2):243-250. doi:10.1136/gutjnl-2020-322200
84. Kim J, Wang TC. Helicobacter pylori and Gastric Cancer. Gastrointest Endosc Clin N Am. 2021;31(3):451-465. doi:10.1016/j.giec.2021.03.003
85. Henle FGJ. Von Den Miasmen Und Kontagien Und von Den Miasmatisch-Kontagiösen Krankheiten. Verlag von August Hirschwald; 1840.
86. Koch HHR. Untersuchungen Über Die Aetiologie Der Wundinfectionskrankheiten. Verlag von F. C. W. Vogel; 1878. https://doi.org/10.17192/eb2013.0081
2. Moodley Y, Linz B, Bond RP, et al. Age of the association between Helicobacter pylori and man. PLoS Pathog. 2012;8(5):e1002693. doi:10.1371/journal.ppat.1002693
3. Yamaoka Y. Helicobacter pylori typing as a tool for tracking human migration. Clin Microbiol Infect. 2009;15(9):829-834. doi:10.1111/j.1469-0691.2009.02967.x
4. Maixner F, Krause-Kyora B, Turaev D, et al. The 5300-year-old Helicobacter pylori genome of the Iceman. Science. 2016;351(6269):162-165. doi:10.1126/science.aad2545
5. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1(8390):1311-1315. doi:10.1016/s0140-6736(84)91816-6
6. Hooi JKY, Lai WY, Ng WK, et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology. 2017;153(2):420-429. doi:10.1053/j.gastro.2017.04.022
7. Coelho LGV, Marinho JR, Genta R, et al. IV th brazilian consensus conference on helicobacter pylori infection. Arq Gastroenterol. 2018;55(2):97-121. doi:10.1590/S0004-2803.201800000-20
8. Sjomina O, Pavlova J, Niv Y, Leja M. Epidemiology of Helicobacter pylori infection. Helicobacter. 2018;23 Suppl 1:e12514. doi:10.1111/hel.12514
9. Sgambato D, Visciola G, Ferrante E, et al. Prevalence of Helicobacter pylori infection in sexual partners of H. pylori-infected subjects: Role of gastroesophageal reflux. United European Gastroenterol J. 2018;6(10):1470-1476. doi:10.1177/2050640618800628
10. Mladenova I, Durazzo M. Transmission of Helicobacter pylori. Minerva Gastroenterol Dietol. 2018;64(3):251-254. doi:10.23736/S1121-421X.18.02480-7
11. Ata AA, Kamel IA. Primary reticulum cell sarcoma of the liver. A case report. J Egypt Med Assoc. 1965;48(7):514-521.
12. Violeta Filip P, Cuciureanu D, Sorina Diaconu L, Maria Vladareanu A, Silvia Pop C. MALT lymphoma: epidemiology, clinical diagnosis and treatment. J Med Life. 2018;11(3):187-193. doi:10.25122/jml-2018-0035
13. Barukčić I. Helicobacter pylori—The Cause of Human Gastric Cancer. Journal of Biosciences and Medicines. 2017;5(2):1-9. doi:10.4236/jbm.2017.52001
14. Barukčić I. Helicobacter Pylori is the Cause of Gastric Cancer. Modern Health Science. 2018;1(1):43-50. doi:10.30560/mhs.v1n1p43
15. IARC. Schistosomes, liver flukes and Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241.
16. Rokkas T, Rokka A, Portincasa P. A systematic review and meta-analysis of the role of Helicobacter pylori eradication in preventing gastric cancer. Ann Gastroenterol. 2017;30(4):414-423. doi:10.20524/aog.2017.0144
17. Ford AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut. 2020;69(12):2113-2121. doi:10.1136/gutjnl-2020-320839
18. Epstein MA, Achong BG, Barr YM. Virus Particles in Cultured Lymphoblasts from Burkitt’s Lymphoma. Lancet. 1964;283(7335):702-703. doi:https://doi.org/10.1016/S0140-6736(64)91524-7
19. Kume T, Oshima K, Shinohara T, et al. Low rate of apoptosis and overexpression of bcl-2 in Epstein-Barr virus-associated gastric carcinoma. Histopathology. 1999;34(6):502-509. doi:10.1111/j.1365-2559.1999.00686.x
20. Chen XZ, Chen H, Castro FA, Hu JK, Brenner H. Epstein-Barr virus infection and gastric cancer: a systematic review. Medicine (Baltimore). 2015;94(20):e792. doi:10.1097/MD.0000000000000792
21. Dombre C, Guyot N, Moreau T, et al. Egg serpins: The chicken and/or the egg dilemma. Semin Cell Dev Biol. 2017;62:120-132. doi:10.1016/j.semcdb.2016.08.019
22. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med. 2009;3(3):e123-130.
23. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. doi:10.1371/journal.pmed.1000100
24. Ishaq S, Nunn L. Helicobacter pylori and gastric cancer: a state of the art review. Gastroenterol Hepatol Bed Bench. 2015;8(Suppl 1):S6-S14.
25. Eslick GD. Helicobacter pylori infection causes gastric cancer? A review of the epidemiological, meta-analytic, and experimental evidence. World J Gastroenterol. 2006;12(19):2991-2999. doi:10.3748/wjg.v12.i19.2991
26. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784-789. doi:10.1056/NEJMoa001999
27. Miki K. Gastric cancer screening by combined assay for serum anti-Helicobacter pylori IgG antibody and serum pepsinogen levels - “ABC method.” Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(7):405-414. doi:10.2183/pjab.87.405
28. Yoshida T, Kato J, Inoue I, et al. Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer. Int J Cancer. 2014;134(6):1445-1457. doi:10.1002/ijc.28470
29. Shuto M, Fujioka T, Matsunari O, et al. Association between Gastric Cancer Risk and Serum Helicobacter pylori Antibody Titers. Gastroenterol Res Pract. 2017;2017:1286198. doi:10.1155/2017/1286198
30. Barukčić I. The Mathematical Formula of the Causal Relationship k. IJAPM. 2016;6(2):45-65. doi:10.17706/ijapm.2016.6.2.45-65
31. Barukčić I. Die Kausalität. 1. Aufl. Wiss.-Verl; 1989.
32. Barukčić I. Die Kausalität. 2., völlig überarb. Aufl. Scientia; 1997.
33. Barukčić I. Theoriae Causalitatis Principia Mathematica. Second edition. Books on Demand GmbH; 2021.
34. Barukčić I. Causal relationship k. International Journal of Mathematics Trends and Technology IJMTT. 2020;66(10):76-115.
35. Barukčić I. The causal relationship k. MATEC Web Conf. 2021;336(2):09032. doi:10.1051/matecconf/202133609032
36. Uspensky JV. Introduction to Mathematical Probability. 1st Edition. McGraw-Hill; 1937.
37. Tschébychef PL. Des valeurs moyennes. Journal de Mathématiques Pures et Appliquées. 1867;12(2):177-184. doi:http://sites.mathdoc.fr/JMPA/PDF/JMPA_1867_2_12_A11_0.pdf
38. Barukčić I. Conditio Sine qua Non. Zenodo; 2022. doi:10.5281/zenodo.5854744
39. Spendel G. Die Kausalitätsformel Der Bedingungstheorie Für Die Handlungsdelikte: Eine Kritische Untersuchung Der Conditio-Sine-qua-Non-Formel Im Strafrecht. Univ. Diss.; 1948.
40. Barukčić I. Conditio per quam. Causation. 2022;17(3):5-86. doi:10.5281/zenodo.6369831
41. Barukčić I. Mutually exclusive events. Causation. 2021;16(11):5-57. doi:10.5281/zenodo.5746415
42. Barukčić I. Cytomegalovirus and lung cancer - a causal relationship? Causation. 2023;18(11):5-30. doi:https://doi.org/10.5281/zenodo.7548139
43. Helmert FR. Ueber die Wahrscheinlichkeit der Potenzsummen der Beobachtungsfehler und über einige damit im Zusammenhange stehende Fragen. Zeitschrift für Mathematik und Physik. 1876;21(3):102-219.
44. Pearson K. X. On the criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be reasonably supposed to have arisen from random sampling. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science. 1900;50(302):157-175.
45. Yates F. Contingency Tables Involving Small Numbers and the χ 2 Test. The Journal of the Royal Statistical Society (Supplement). 1934;1(2):217. doi:10.2307/2983604
46. Barukčić I. The P Value of likely extreme events. International Journal of Current Science Research. 2019;5(11):1841-1861.
47. Cornfield J. A method of estimating comparative rates from clinical data; applications to cancer of the lung, breast, and cervix. Journal of the National Cancer Institute. 1951;11(6):1269-1275.
48. Sadowsky DA, Gilliam AG, Cornfield J. The statistical association between smoking and carcinoma of the lung. J Natl Cancer Inst. 1953;13(5):1237-1258.
49. Barukčić I. The logical content of the risk ratio. Causation. 2021;16(4):5-41. doi:10.5281/zenodo.4679509
50. Yule GU. On the Association of Attributes in Statistics: With Illustrations from the Material of the Childhood Society, &c. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. 1900;194(252-261):257-319. doi:10.1098/rsta.1900.0019
51. Fisher RA. The Logic of Inductive Inference. Journal of the Royal Statistical Society. 1935;98(1):39-82. doi:10.2307/2342435
52. Cox DR. The Regression Analysis of Binary Sequences. Journal of the Royal Statistical Society Series B (Methodological). 1958;20(2):215-242.
53. Yule GU. On the Methods of Measuring Association Between Two Attributes. Journal of the Royal Statistical Society. 1912;75(6):579. doi:10.2307/2340126
54. Barukčić I. Index of relationship. Causation. 2021;16(8):5-37. doi:10.5281/zenodo.5163179
55. Barukčić I. Index of Unfairness. Modern Health Science. 2019;2(1):22-59. doi:10.30560/mhs.v2n1p22
56. Barukčić I. Conditions and study design. Causation. 2022;18(1):5-99. doi:10.5281/zenodo.6816088
57. Barukčić I. Causal Inference and Study Design. Zenodo; 2022. doi:10.5281/zenodo.6299686
58. Pearson K. XV. On certain properties of the hypergeometrical series, and on the fitting of such series to observation polygons in the theory of chance. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science. 1899;47(285):236-246. doi:10.1080/14786449908621253
59. Gonin HT. XIV. The use of factorial moments in the treatment of the hypergeometric distribution and in tests for regression. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science. 1936;21(139):215-226. doi:10.1080/14786443608561573
60. Pólya G. Über den zentralen Grenzwertsatz der Wahrscheinlichkeitsrechnung und das Momentenproblem: [In English: On the central limit theorem of probability calculation and the problem of moments]. Mathematische Zeitschrift. 1920;8(3-4):171-181. doi:10.1007/BF01206525
61. Barukčić I. Theoriae Causalitatis Principia Mathematica. First edition. Books on Demand GmbH; 2017.
62. Barukčić I. Unified Field Theory. Journal of Applied Mathematics and Physics. 2016;4(8):1379-1438. doi:10.4236/jamp.2016.48147
63. Barukčić I. Index of Independence. Modern Health Science. 2019;2(2):1-25. doi:10.30560/mhs.v2n2p1
64. Bergh D. Chi-Squared Test of Fit and Sample Size-A Comparison between a Random Sample Approach and a Chi-Square Value Adjustment Method. Journal of Applied Measurement. 2015;16(2):204-217.
65. Bonferroni CE. Teoria statistica delle classi e calcolo delle probabilità. Seeber; 1936.
66. Takada K. Epstein-Barr virus and gastric carcinoma. Mol Pathol. 2000;53(5):255-261. doi:10.1136/mp.53.5.255
67. Gall JG, Pardue ML. Formation and detection of RNA-DNA hybrid molecules in cytological preparations. Proceedings of the National Academy of Sciences of the United States of America. 1969;63(2):378-383. doi:10.1073/pnas.63.2.378
68. Jensen E. Technical review: In situ hybridization. Anat Rec (Hoboken). 2014;297(8):1349-1353. doi:10.1002/ar.22944
69. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953;171(4356):737-738. doi:10.1038/171737a0
70. Walker PJ, Siddell SG, Lefkowitz EJ, et al. Changes to virus taxonomy and to the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2021). Arch Virol. 2021;166(9):2633-2648. doi:10.1007/s00705-021-05156-1
71. Feederle R, Klinke O, Kutikhin A, Poirey R, Tsai MH, Delecluse HJ. Epstein-Barr Virus: From the Detection of Sequence Polymorphisms to the Recognition of Viral Types. Curr Top Microbiol Immunol. 2015;390(Pt 1):119-148. doi:10.1007/978-3-319-22822-8_7
72. Babcock GJ, Decker LL, Volk M, Thorley-Lawson DA. EBV persistence in memory B cells in vivo. Immunity. 1998;9(3):395-404.
73. Miyashita EM, Yang B, Babcock GJ, Thorley-Lawson DA. Identification of the site of Epstein-Barr virus persistence in vivo as a resting B cell. J Virol. 1997;71(7):4882-4891. doi:10.1128/JVI.71.7.4882-4891.1997
74. Amon W, Farrell PJ. Reactivation of Epstein-Barr virus from latency. Rev Med Virol. 2005;15(3):149-156. doi:10.1002/rmv.456
75. Cui J, Yan W, Xu S, et al. Anti-Epstein-Barr virus antibodies in Beijing during 2013-2017: What we have found in the different patients. PLoS One. 2018;13(3):e0193171. doi:10.1371/journal.pone.0193171
76. Garaud S, Buisseret L, Solinas C, et al. Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight. 2019;5(18):e129641, 129641. doi:10.1172/jci.insight.129641
77. David H. Rudolf Virchow and modern aspects of tumor pathology. Pathol Res Pract. 1988;183(3):356-364. doi:10.1016/S0344-0338(88)80138-9
78. Whitford P, Mallon EA, George WD, Campbell AM. Flow cytometric analysis of tumour infiltrating lymphocytes in breast cancer. Br J Cancer. 1990;62(6):971-975. doi:10.1038/bjc.1990.419
79. Barukčić I. Gastric Cancer and Epstein-Barr Virus Infection. Modern Health Science. 2018;1(2):1-18. doi:10.30560/mhs.v1n2p1
80. Peek RM, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol. 2006;208(2):233-248. doi:10.1002/path.1868
81. Peek RM, Fiske C, Wilson KT. Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiol Rev. 2010;90(3):831-858. doi:10.1152/physrev.00039.2009
82. Wong BCY, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004;291(2):187-194. doi:10.1001/jama.291.2.187
83. Chiang TH, Chang WJ, Chen SLS, et al. Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands. Gut. 2021;70(2):243-250. doi:10.1136/gutjnl-2020-322200
84. Kim J, Wang TC. Helicobacter pylori and Gastric Cancer. Gastrointest Endosc Clin N Am. 2021;31(3):451-465. doi:10.1016/j.giec.2021.03.003
85. Henle FGJ. Von Den Miasmen Und Kontagien Und von Den Miasmatisch-Kontagiösen Krankheiten. Verlag von August Hirschwald; 1840.
86. Koch HHR. Untersuchungen Über Die Aetiologie Der Wundinfectionskrankheiten. Verlag von F. C. W. Vogel; 1878. https://doi.org/10.17192/eb2013.0081