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Personalized inherent randomness of the immune system is manifested by an individualized response to immune triggers and immunomodulatory therapies: a novel platform for designing personalized immunotherapies

  • Madi El-Haj
  • Dimitri Kanovitch
  • Yaron IlanEmail author
Original Article
  • 22 Downloads

Abstract

The considerable variability of responses amongst subjects to disease triggers and immunotherapies is a major obstacle to designing better immune-based therapies. Therefore, development of patient-tailored precision medicine that improves the efficacy of immunomodulatory drugs is necessary. The individualized response to disease triggers and immunomodulatory therapies was studied using the concanavalin A (ConA) immune-mediated hepatitis model and the oral administration of anti CD3 or β-glucosylceramide (GC). Mice were treated with anti-CD3 antibodies or GC followed by an injection of ConA. The effects of these treatments on liver damage and the immune profile were then analyzed. An individualized response to ConA and orally administered immunomodulatory agents was observed in eight consecutive experiments. While alleviation of the immune-mediated liver injury, as measured by serum levels of liver enzymes, was seen, and high intra-group and inter-experimental variabilities were detected. A similar individualized response was observed for the effect on serum levels of IFN-γ, TNF-α, and IL-10 and on CD4+CD25+, CD8+CD25+, and CD3+NK1.1+ lymphocytes. A personalized form of inherent randomness in an isolated system was documented, which may underlie the variability in responses to immune triggers and immunomodulatory therapies. The data support the use of personalized randomness-based platforms for improving the response to chronic therapies.

Keywords

Precision medicine Patient-tailored therapy Autoimmune disease Immunomodulation NKT cells 

Abbreviations

GC

β-glucosylceramide

ConA

Concanavalin A

NKT

Natural killer T

AST

Aspartate aminotransferase

ALT

Alanine aminotransferase

IFN-γ

Interferon gamma

TNF-α

Tumor necrosis factor alpha

IL10

Interleukin 10

PDL1

Programmed death-ligand 1

PD

Programmed death-1

Notes

Compliance with ethical standards

Animal experiments were carried out according to the guidelines of the Hebrew University-Hadassah Institutional Committee for the Care and Use of Laboratory Animals and with the committee’s approval.

Conflict of interest

YI is a founder of Oberon Sciences and consultant for Teva, ENZO, Protalix, Betalin Therapeutics, Immuron, SciM, Natural Shield, Tiziana Pharma, Plantylight, and Exalenz Bioscience.

Supplementary material

12026_2019_9101_MOESM1_ESM.xls (86 kb)
ESM 1 (XLS 85 kb)

References

  1. 1.
    Kucuksezer UC, Ozdemir C, Akdis M, Akdis CA. Precision/Personalized Medicine in Allergic Diseases and Asthma. Arch Immunol Ther Exp. 2018;66:431–42.  https://doi.org/10.1007/s00005-018-0526-6.CrossRefGoogle Scholar
  2. 2.
    Doestzada M, Vila AV, Zhernakova A, Koonen DPY, Weersma RK, Touw DJ, et al. Pharmacomicrobiomics: a novel route towards personalized medicine? Protein Cell. 2018;9(5):432–45.  https://doi.org/10.1007/s13238-018-0547-2.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Currie G, Delles C. Precision Medicine and Personalized Medicine in Cardiovascular Disease. Adv Exp Med Biol. 2018;1065:589–605.  https://doi.org/10.1007/978-3-319-77932-4_36.CrossRefPubMedGoogle Scholar
  4. 4.
    Tavakolpour S. Towards personalized medicine for patients with autoimmune diseases: Opportunities and challenges. Immunol Lett. 2017;190:130–8.  https://doi.org/10.1016/j.imlet.2017.08.002.CrossRefPubMedGoogle Scholar
  5. 5.
    Doria A, Gershwin ME, Selmi C. From old concerns to new advances and personalized medicine in lupus: The end of the tunnel is approaching. J Autoimmun. 2016;74:1–5.  https://doi.org/10.1016/j.jaut.2016.08.007.CrossRefPubMedGoogle Scholar
  6. 6.
    Biesen R, Rose T, Hoyer BF, Alexander T, Hiepe F. Autoantibodies, complement and type I interferon as biomarkers for personalized medicine in SLE. Lupus. 2016;25(8):823–9.  https://doi.org/10.1177/0961203316640922.CrossRefPubMedGoogle Scholar
  7. 7.
    Bauer C, Stec K, Glintschert A, Gruden K, Schichor C, Or-Guil M, et al. BioMiner: Paving the Way for Personalized Medicine. Cancer Informat. 2015;14:55–63.  https://doi.org/10.4137/CIN.S20910.CrossRefGoogle Scholar
  8. 8.
    Wardill HR, Tissing WJE. Determining risk of severe gastrointestinal toxicity based on pretreatment gut microbial community in patients receiving cancer treatment: a new predictive strategy in the quest for personalized cancer medicine. Curr Opin Support Palliat Care. 2017;11(2):125–32.  https://doi.org/10.1097/SPC.0000000000000265.CrossRefPubMedGoogle Scholar
  9. 9.
    Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury. Z Gastroenterol. 2007;45(1):63–70.CrossRefGoogle Scholar
  10. 10.
    Erhardt A, Biburger M, Papadopoulos T, Tiegs G. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology. 2007;45(2):475–85.CrossRefGoogle Scholar
  11. 11.
    Margalit M, Ghazala SA, Alper R, Elinav E, Klein A, Doviner V, et al. Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes. Am J Physiol Gastrointest Liver Physiol. 2005;289(5):G917–25.CrossRefGoogle Scholar
  12. 12.
    Ogura M, Deng S, Preston-Hurlburt P, Ogura H, Shailubhai K, Kuhn C, et al. Oral treatment with foralumab, a fully human anti-CD3 monoclonal antibody, prevents skin xenograft rejection in humanized mice. Clin Immunol. 2017;183:240–6.  https://doi.org/10.1016/j.clim.2017.07.005.CrossRefPubMedGoogle Scholar
  13. 13.
    Kuhn C, Weiner HL. Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. Immunotherapy. 2016;8(8):889–906.  https://doi.org/10.2217/imt-2016-0049.CrossRefPubMedGoogle Scholar
  14. 14.
    da Cunha AP, Weiner HL. Induction of immunological tolerance by oral anti-CD3. Clin Dev Immunol. 2012;2012:425021.  https://doi.org/10.1155/2012/425021.CrossRefPubMedGoogle Scholar
  15. 15.
    Wu HY, Maron R, Tukpah AM, Weiner HL. Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant. J Immunol. 2010;185(6):3401–7.  https://doi.org/10.4049/jimmunol.1000836.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ilan Y, Maron R, Tukpah AM, Maioli TU, Murugaiyan G, Yang K, et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc Natl Acad Sci U S A. 2010;107(21):9765–70.  https://doi.org/10.1073/pnas.0908771107.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Abraham M, Karni A, Dembinsky A, Miller A, Gandhi R, Anderson D, et al. In vitro induction of regulatory T cells by anti-CD3 antibody in humans. J Autoimmun. 2008;30(1-2):21–8.  https://doi.org/10.1016/j.jaut.2007.11.007.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ilan Y, Shailubhai K, Sanyal A. Immunotherapy with oral administration of humanized anti-CD3 monoclonal antibody: a novel gut-immune system-based therapy for metaflammation and NASH. Clin Exp Immunol. 2018;193(3):275–83.  https://doi.org/10.1111/cei.13159.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ilan Y. Review article: novel methods for the treatment of non-alcoholic steatohepatitis - targeting the gut immune system to decrease the systemic inflammatory response without immune suppression. Aliment Pharmacol Ther. 2016;44(11-12):1168–82.  https://doi.org/10.1111/apt.13833.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ilan Y, Zigmond E, Lalazar G, Dembinsky A, Ben Ya'acov A, Hemed N, et al. Oral administration of OKT3 monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells. J Clin Immunol. 2010;30(1):167–77.  https://doi.org/10.1007/s10875-009-9323-7.CrossRefPubMedGoogle Scholar
  21. 21.
    Lalazar G, Mizrahi M, Turgeman I, Adar T, Ben Ya'acov A, Shabat Y, et al. Oral Administration of OKT3 MAb to Patients with NASH, Promotes Regulatory T-cell Induction, and Alleviates Insulin Resistance: Results of a Phase IIa Blinded Placebo-Controlled Trial. J Clin Immunol. 2015;35(4):399–407.  https://doi.org/10.1007/s10875-015-0160-6.CrossRefPubMedGoogle Scholar
  22. 22.
    Halota W, Ferenci P, Kozielewicz D, Dybowska D, Lisovoder N, Samira S, et al. Oral anti-CD3 immunotherapy for HCV-nonresponders is safe, promotes regulatory T cells and decreases viral load and liver enzyme levels: results of a phase-2a placebo-controlled trial. J Viral Hepat. 2015;22(8):651–7.  https://doi.org/10.1111/jvh.12369.CrossRefPubMedGoogle Scholar
  23. 23.
    Ilan Y. Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2016;310(11):G1102–17.  https://doi.org/10.1152/ajpgi.00095.2016.CrossRefPubMedGoogle Scholar
  24. 24.
    Zigmond E, Tayer-Shifman O, Lalazar G, Ben Ya'acov A, Weksler-Zangen S, Shasha D, et al. beta-glycosphingolipids ameliorated non-alcoholic steatohepatitis in the Psammomys obesus model. J Inflamm Res. 2014;7:151–8.  https://doi.org/10.2147/JIR.S50508.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Zigmond E, Zangen SW, Pappo O, Sklair-Levy M, Lalazar G, Zolotaryova L, et al. Beta-glycosphingolipids improve glucose intolerance and hepatic steatosis of the Cohen diabetic rat. Am J Physiol. 2009;296(1):E72–8.  https://doi.org/10.1152/ajpendo.90634.2008.CrossRefGoogle Scholar
  26. 26.
    Zhang W, Moritoki Y, Tsuneyama K, Yang GX, Ilan Y, Lian ZX, et al. Beta-glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis. Clin Exp Immunol. 2009;157(3):359–64.  https://doi.org/10.1111/j.1365-2249.2009.03971.x.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shuvy M, Ben Ya'acov A, Zolotarov L, Lotan C, Ilan Y. Beta glycosphingolipids suppress rank expression and inhibit natural killer T cell and CD8+ accumulation in alleviating aortic valve calcification. Int J Immunopathol Pharmacol. 2009;22(4):911–8.  https://doi.org/10.1177/039463200902200406.CrossRefPubMedGoogle Scholar
  28. 28.
    Lalazar G, Ben Ya'acov A, Livovsky DM, El Haj M, Pappo O, Preston S, et al. Beta-glycoglycosphingolipid-induced alterations of the STAT signaling pathways are dependent on CD1d and the lipid raft protein flotillin-2. Am J Pathol. 2009;174(4):1390–9.  https://doi.org/10.2353/ajpath.2009.080841.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ben Ya'acov A, Lalazar G, Livovsky DM, Kanovich D, Axelrod E, Preston S, et al. Decreased STAT-1 phosphorylation by a thio analogue of beta-D-glucosylceramide is associated with altered NKT lymphocyte polarization. Mol Immunol. 2009;47(2-3):526–33.  https://doi.org/10.1016/j.molimm.2009.07.030.CrossRefPubMedGoogle Scholar
  30. 30.
    Zigmond E, Shalev Z, Pappo O, Alper R, Zolotarov L, Ilan Y. NKT lymphocyte polarization determined by microenvironment signaling: a role for CD8+ lymphocytes and beta-glycosphingolipids. J Autoimmun. 2008;31(2):188–95.  https://doi.org/10.1016/j.jaut.2008.07.003.CrossRefPubMedGoogle Scholar
  31. 31.
    Livovsky DM, Lalazar G, Ben Ya'acov A, Pappo O, Preston S, Zolotaryova L, et al. Administration of beta-glycolipids overcomes an unfavorable nutritional dependent host milieu: a role for a soy-free diet and natural ligands in intrahepatic CD8+ lymphocyte trapping and NKT cell redistribution. Int Immunopharmacol. 2008;8(9):1298–305.  https://doi.org/10.1016/j.intimp.2008.05.005.CrossRefPubMedGoogle Scholar
  32. 32.
    Lalazar G, Ben Ya'acov A, Eliakim-Raz N, Livovsky DM, Pappo O, Preston S, et al. Beta-glycosphingolipids-mediated lipid raft alteration is associated with redistribution of NKT cells and increased intrahepatic CD8+ T lymphocyte trapping. J Lipid Res. 2008;49(9):1884–93.  https://doi.org/10.1194/jlr.M800113-JLR200.CrossRefPubMedGoogle Scholar
  33. 33.
    Zigmond E, Preston S, Pappo O, Lalazar G, Margalit M, Shalev Z, et al. Beta-glucosylceramide: a novel method for enhancement of natural killer T lymphoycte plasticity in murine models of immune-mediated disorders. Gut. 2007;56(1):82–9.CrossRefGoogle Scholar
  34. 34.
    Lalazar G, Zigmond E, Weksler-Zangen S, Ya'acov AB, Levy MS, Hemed N, et al. Oral Administration of beta-Glucosylceramide for the Treatment of Insulin Resistance and Nonalcoholic Steatohepatitis: Results of a Double-Blind. Placebo-Controlled Trial J Med Food. 2017;20(5):458–64.  https://doi.org/10.1089/jmf.2016.3753.CrossRefPubMedGoogle Scholar
  35. 35.
    Ilan Y, Ohana M, Pappo O, Margalit M, Lalazar G, Engelhardt D, et al. Alleviation of acute and chronic graft-versus-host disease in a murine model is associated with glucocerebroside-enhanced natural killer T lymphocyte plasticity. Transplantation. 2007;83(4):458–67.CrossRefGoogle Scholar
  36. 36.
    Lalazar G, Preston S, Zigmond E, Ben Yaacov A, Ilan Y. Glycolipids as immune modulatory tools. Mini-Rev Med Chem. 2006;6(11):1249–53.CrossRefGoogle Scholar
  37. 37.
    Safadi R, Zigmond E, Pappo O, Shalev Z, Ilan Y. Amelioration of hepatic fibrosis via beta-glucosylceramide-mediated immune modulation is associated with altered CD8 and NKT lymphocyte distribution. Int Immunol. 2007;19(8):1021–9.CrossRefGoogle Scholar
  38. 38.
    Lalazar G, Ben Ya'acov A, Lador A, Livovsky DM, Pappo O, Preston S, et al. Modulation of intracellular machinery by beta-glycolipids is associated with alteration of NKT lipid rafts and amelioration of concanavalin-induced hepatitis. Mol Immunol. 2008;45(13):3517–25.  https://doi.org/10.1016/j.molimm.2008.05.009.CrossRefPubMedGoogle Scholar
  39. 39.
    Mizrahi M, Lalazar G, Ben Ya'acov A, Livovsky DM, Horowitz Y, Zolotarov L, et al. Beta-glycoglycosphingolipid-induced augmentation of the anti-HBV immune response is associated with altered CD8 and NKT lymphocyte distribution: a novel adjuvant for HBV vaccination. Vaccine. 2008;26(21):2589–95.  https://doi.org/10.1016/j.vaccine.2008.03.026.CrossRefPubMedGoogle Scholar
  40. 40.
    Elinav E, Pappo O, Sklair-Levy M, Margalit M, Shibolet O, Gomori M, et al. Amelioration of non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice by oral immune regulation towards liver-extracted proteins is associated with elevated intrahepatic NKT lymphocytes and serum IL-10 levels. J Pathol. 2006;208(1):74–81.  https://doi.org/10.1002/path.1869.CrossRefPubMedGoogle Scholar
  41. 41.
    Dennert G, Aswad F. The role of NKT cells in animal models of autoimmune hepatitis. Crit Rev Immunol. 2006;26(5):453–73.CrossRefGoogle Scholar
  42. 42.
    Halder RC, Aguilera C, Maricic I, Kumar V. Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease. J Clin Invest. 2007;117(8):2302–12.CrossRefGoogle Scholar
  43. 43.
    Kawamura T, Takeda K, Kaneda H, Matsumoto H, Hayakawa Y, Raulet DH, et al. NKG2A inhibits invariant NKT cell activation in hepatic injury. J Immunol. 2009;182(1):250–8.CrossRefGoogle Scholar
  44. 44.
    Hov JR, Karlsen TH. The Microbiome in Primary Sclerosing Cholangitis: Current Evidence and Potential Concepts. Semin Liver Dis. 2017;37(4):314–31.  https://doi.org/10.1055/s-0037-1608801.CrossRefPubMedGoogle Scholar
  45. 45.
    Goulart LR, Santos PS, Carneiro AP, Santana BB, Vallinoto AC, Araujo TG. Unraveling Antibody Display: Systems Biology and Personalized Medicine. Curr Pharm Des. 2016;22(43):6560–76.  https://doi.org/10.2174/1381612822666160923112816.CrossRefPubMedGoogle Scholar
  46. 46.
    Aabakken L, Karlsen TH, Albert J, Arvanitakis M, Chazouilleres O, Dumonceau JM, et al. Role of endoscopy in primary sclerosing cholangitis: European Society of Gastrointestinal Endoscopy (ESGE) and European Association for the Study of the Liver (EASL) Clinical Guideline. Endoscopy. 2017;49(6):588–608.  https://doi.org/10.1055/s-0043-107029.CrossRefPubMedGoogle Scholar
  47. 47.
    Li S, Todor A, Luo R. Blood transcriptomics and metabolomics for personalized medicine. Comput Struct Biotechnol J. 2016;14:1–7.  https://doi.org/10.1016/j.csbj.2015.10.005.CrossRefPubMedGoogle Scholar
  48. 48.
    Sirotti S, Generali E, Ceribelli A, Isailovic N, De Santis M, Selmi C. Personalized medicine in rheumatology: the paradigm of serum autoantibodies. Auto Immun Highlights. 2017;8(1):10–3.  https://doi.org/10.1007/s13317-017-0098-1.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Chen P, Huang NT, Chung MT, Cornell TT, Kurabayashi K. Label-free cytokine micro- and nano-biosensing towards personalized medicine of systemic inflammatory disorders. Adv Drug Deliv Rev. 2015;95:90–103.  https://doi.org/10.1016/j.addr.2015.09.005.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Brzustewicz E, Bzoma I, Daca A, Szarecka M, Bykowska MS, Witkowski JM, et al. Heterogeneity of the cytokinome in undifferentiated arthritis progressing to rheumatoid arthritis and its change in the course of therapy. Move toward personalized medicine. Cytokine. 2017;97:1–13.  https://doi.org/10.1016/j.cyto.2017.05.012.CrossRefPubMedGoogle Scholar
  51. 51.
    Rodriguez-Carrio J, Lopez P, Suarez A. EPC dysfunction and immune networks: translating opportunities for the clinical setting in personalized medicine. Curr Med Chem. 2017.  https://doi.org/10.2174/0929867324666170606101823.CrossRefGoogle Scholar
  52. 52.
    Sui H, Ma N, Wang Y, Li H, Liu X, Su Y, et al. Anti-PD-1/PD-L1 Therapy for Non-Small-Cell Lung Cancer: Toward Personalized Medicine and Combination Strategies. J Immunol Res. 2018;2018:6984948.  https://doi.org/10.1155/2018/6984948.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ilan Y. Advanced Tailored Randomness: A Novel Approach for Improving the Efficacy of Biological Systems. J Comput Biol. 2019.  https://doi.org/10.1089/cmb.2019.0231.
  54. 54.
    Ilan Y. Why targeting the microbiome is not so successful: can randomness overcome the adaptation that occurs following gut manipulation? Clin Exp Gastroenterol. 2019;12:209–17.  https://doi.org/10.2147/CEG.S203823.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ilan Y. beta-Glycosphingolipids as Mediators of Both Inflammation and Immune Tolerance: A Manifestation of Randomness in Biological Systems. Front Immunol. 2019;10:1143.  https://doi.org/10.3389/fimmu.2019.01143.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ilan Y. Randomness in microtubule dynamics: an error that requires correction or an inherent plasticity required for normal cellular function? Cell Biol Int. 2019;43(7):739–48.  https://doi.org/10.1002/cbin.11157.CrossRefPubMedGoogle Scholar
  57. 57.
    Ilan Y. Generating randomness: making the most out of disordering a false order into a real one. J Transl Med. 2019;17(1):49–12.  https://doi.org/10.1186/s12967-019-1798-2.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Buiatti M, Buiatti M. Chance vs. necessity in living systems: a false antinomy. Riv Biol. 2008;101(1):29–66.PubMedGoogle Scholar
  59. 59.
    Montevil M, Mossio M, Pocheville A, Longo G. Theoretical principles for biology: Variation. Prog Biophys Mol Biol. 2016;122(1):36–50.  https://doi.org/10.1016/j.pbiomolbio.2016.08.005.CrossRefPubMedGoogle Scholar
  60. 60.
    Buiatti M, Longo G. Randomness and multilevel interactions in biology. Theory Biosci. 2013;132(3):139–58.  https://doi.org/10.1007/s12064-013-0179-2.CrossRefPubMedGoogle Scholar
  61. 61.
    Longo G, Montevil M, Sonnenschein C, Soto AM. In search of principles for a Theory of Organisms. J Biosci. 2015;40(5):955–68.CrossRefGoogle Scholar
  62. 62.
    Longo G, Montevil M, Pocheville A. From bottom-up approaches to levels of organization and extended critical transitions. Front Physiol. 2012;3:232.  https://doi.org/10.3389/fphys.2012.00232.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Vinks AA. Precision Medicine-Nobody Is Average. Clin Pharmacol Ther. 2017;101(3):304–7.  https://doi.org/10.1002/cpt.600.CrossRefPubMedGoogle Scholar
  64. 64.
    West J. Where Medicine Went Wrong: Rediscovering the Path to Complexity: Studies of Nonlinear Phenomena in Life Science. 2006.CrossRefGoogle Scholar
  65. 65.
    Wu L, Jiang Z, Li C, Shu M. Prediction of heart rate variability on cardiac sudden death in heart failure patients: a systematic review. Int J Cardiol. 2014;174(3):857–60.  https://doi.org/10.1016/j.ijcard.2014.04.176.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Sima CA, Inskip JA, Sheel AW, van Eeden SF, Reid WD, Camp PG. The reliability of short-term measurement of heart rate variability during spontaneous breathing in people with chronic obstructive pulmonary disease. Rev Port Pneumol (2006). 2017;23(6):338–42.  https://doi.org/10.1016/j.rppnen.2017.06.001.CrossRefGoogle Scholar
  67. 67.
    Dingwell JB, John J, Cusumano JP. Do humans optimally exploit redundancy to control step variability in walking? PLoS Comput Biol. 2010;6(7):e1000856.  https://doi.org/10.1371/journal.pcbi.1000856.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Godfrey DI, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest. 2004;114(10):1379–88.CrossRefGoogle Scholar
  69. 69.
    Motulsky HJ. Common misconceptions about data analysis and statistics. Pharmacol Res Perspect. 2015;3(1):e00093.  https://doi.org/10.1002/prp2.93.CrossRefPubMedGoogle Scholar
  70. 70.
    Robertson D, Cook D. Unrealistic statistics: how average constitutive coefficients can produce non-physical results. J Mech Behav Biomed Mater. 2014;40:234–9.  https://doi.org/10.1016/j.jmbbm.2014.09.006.CrossRefPubMedGoogle Scholar
  71. 71.
    Denny M. The fallacy of the average: on the ubiquity, utility and continuing novelty of Jensen's inequality. J Exp Biol. 2017;220(Pt 2):139–46.  https://doi.org/10.1242/jeb.140368.CrossRefPubMedGoogle Scholar
  72. 72.
    Song YS, Patil A, Murphy EE, Slatkin M. Average probability that a "cold hit" in a DNA database search results in an erroneous attribution. J Forensic Sci. 2009;54(1):22–7.  https://doi.org/10.1111/j.1556-4029.2008.00917.x.CrossRefPubMedGoogle Scholar
  73. 73.
    Beck RW, Connor CG, Mullen DM, Wesley DM, Bergenstal RM. The Fallacy of Average: How Using HbA1c Alone to Assess Glycemic Control Can Be Misleading. Diabetes Care. 2017;40(8):994–9.  https://doi.org/10.2337/dc17-0636.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of MedicineHadassah-Hebrew University Medical CenterJerusalemIsrael

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