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Genetic Discovery, Rigorous Statistics, and Pandemic InfluenzaGenetic Discovery and Pandemic Influenza FREE TO VIEW

Mary Beth Scholand, MD, FCCP; Theodore G. Liou, MD, FCCP
Author and Funding Information

From the Department of Internal Medicine, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, School of Medicine, University of Utah.

Correspondence to: Theodore G. Liou, MD, FCCP, Department of Internal Medicine, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, School of Medicine, University of Utah, 26 NMario Capecchi Dr, Salt Lake City, UT 84132; e-mail: ted.liou@utah.edu


Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Scholand is a member of the American College of Chest Physicians Interstitial Lung Disease Steering Committee. She receives funding from the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) and the University of Utah Genome Project. She is a site principal investigator for clinical trials and in this capacity receives funding from InterMune; Gilead Sciences, Inc; Boehringer-Ingelheim GmbH; Roche; MedImmune; FibroGen, Inc; and Bristol-Meyers Squibb. Dr Liou is a member of the Editorial Board of CHEST and an ad hoc member of the Clinical Research Study Review Committee of the US Cystic Fibrosis Foundation (CFF); he is a recent past member of the Thoracic Committee of the United Network for Organ Sharing/Organization for the Procurement and Transplantation Network, the CFF Patient Registry Data Use Committee, the REVEAL Steering Committee (sponsored by Actelion Pharmaceuticals Ltd), and the National Institute for Occupational Safety and Health World Trade Center Research Review Committee. He has received grant funding from CFF Therapeutics, Inc; the NIH/NHLBI; and the Margolis Family Foundation of Utah; and receives funding for studies of therapies from CFF Therapeutics, Inc; Genentech Inc; Gilead Sciences, Inc; Inspire; MPex Pharmaceuticals, Inc; Savara Pharmaceuticals; and Vertex. He is a consultant for Gehrson Lehman Group, Inc; Genentech Inc; and Vertex.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(6):1186-1188. doi:10.1378/chest.14-0137
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Pandemic influenza threatens public health globally.1 The pandemic 2009 influenza A(H1N1) (A[H1N1]pdm09) caused serious morbidity and high case-fatality rates worldwide: 214 countries reported 18,837 deaths during the first 6 months of 2010.2 Patients with chronic medical conditions were especially prone to poor outcomes,3-5 but this strain of influenza, similar to the 1918 “Spanish” influenza virus in both genetic sequence6 and behavior,7 caused unusually severe effects in young adults. A(H1N1)pdm09 has the additional distinction of producing poor outcomes among pregnant3,4 and obese patients,8 a phenomenon not seen with other recent strains of influenza.

Rapid viral mutation of influenza viruses fuels well-founded fear focused on our inability to control pandemic disease. The 1918 influenza pandemic virus appears to have had an avian origin with specific mutations that conferred high transmissibility and lethality among humans.9 In contrast, A(H1N1)pdm09 resulted from multiple genetic reassortments of swine-origin influenza.

In this issue of CHEST (see page 1237), To et al10 highlight the importance of another component of disease severity, the host response to the pandemic virus isolated from patients in Hong Kong.11 They explore the impact of genetic variation in surfactant B genes on human host responses to influenza and the resultant clinical severity of disease that so frequently causes death from influenza.

Our understanding of surfactant biology is evolving quickly. Surfactants have a host of roles and qualify as members of the growing number of known “moonlighting” proteins.12 Evidence demonstrates that surfactants, including surfactant B, once thought to be primarily responsible for function hysteresis, influence multiple pulmonary processes, including the development of pulmonary fibrosis13 and COPD.14 Surfactants A and D are well documented as playing a role in bacterial, fungal, and viral defense.15 Surfactant B is less well known for its immune properties but now looks to play a critical role in viral defense.

Genetic variation impacts protein structure and the ability of these proteins to perform any one or multiple of their functions. The common variants in our population are gradually being revealed to influence human variable response to disease and environmental stressors. The C allele of single nucleotide polymorphism (SNP) rs1130866 is the common allele, present in 70% of the Han Chinese population studied.16 It is this dominant variant that deleteriously influences the host response to viral infection and provides some insight into the variance in host response to a common but deadly virus. The minor allele appears to be protective in this specific setting.

Genetic variation is only one of many potential factors that can alter clinical outcomes of disease. Rigorous statistical procedures can and should facilitate discovery of those factors and highlight their relative importance. Successful statistical analysis can produce results that identify the most important features of disease for further clinical investigations, guide development of new treatments, and provide deeper insights into disease mechanisms. Using modern technology, To et al10 followed an old path to discovery: formulation of a testable hypothesis, evaluation one by one for univariate statistical associations between potential predictors and outcomes, and, finally, meticulous assessment of the relative importance of potentially independent contributors to the chosen outcome.

Specifically, they hypothesized that surfactant protein genetic variation may influence outcomes in influenza. They evaluated a chosen set of SNPs, searching plausible candidates related to surfactant proteins for an association with severe disease within rigorously controlled conditions. Finally, they assessed the significance of univariate relationships in a more diverse and, therefore, more generalizable group of subjects by means of multivariate analysis to find the relative importance of their selected SNP compared with other independent, potentially causal factors for severe disease. Hypothesis-driven exploration, carefully corrected for multiple comparisons, produced a borderline P value, above the arbitrary threshold of .05. But the hypothesis-driven nature of the study allowed a thoughtful interpretation that identified the SNP as worthy of additional investigation. Multivariate analysis within a larger population of patients replicated the real-world mix of young and old patients with chronic pulmonary, neurologic, cardiac, metabolic, and endocrine disorders and demonstrated true significance.

The multivariate analysis provides three important insights. First, a specific variation in surfactant protein B caused by an SNP, rs1130866, independently affects outcomes for a wide range of patients infected by A(H1N1)pdm09. Second, although obesity played the largest single role in determining severity in their study,8 To et al10 show that the genetic variation associated with surfactant B has an effect on severity comparable in strength to the effects of the other previously discovered major conditions that predispose to poor outcomes with influenza A infection.3 Finally, they show with specific testing that rs1130866 has no association with obesity, clearly showing the independence of their major finding.

The evidence presented by To et al10 provides an additional starting point for studies of mechanisms of pulmonary disease related to the role of surfactant proteins. The strong association of surfactant B with severe responses to infection suggests that further bench investigations might focus on the interaction of surfactants with A(H1N1)pdm09 viral particles.

Perhaps closer to the bedside, their results may help identify a subset of adult patients with acute lung injury and ARDS, an unfortunately common feature of A(H1N1)pdm09 infection,3 who might respond to surfactant therapy. Surfactant therapy fails in adult acute lung injury/ARDS but successfully treats infant respiratory distress syndrome; it is theorized that failure to detect efficacy in adults may be caused by patient heterogeneity.17 With additional data, patients with the common rs1130866 variant suffering ARDS from influenza A infection may prove to be one specific group of patients for whom surfactant therapy may be helpful.

Formulation of a specific testable hypothesis, rigorous study design, careful statistical analysis, and equally careful interpretation of results provide a secure basis for conducting science.18 In this case, To et al10 convincingly show that variation in rs1130866 has a clinically relevant impact on the severity of infection with influenza A in a general population of Chinese patients.

References

Neumann G, Chen H, Gao GF, Shu Y, Kawaoka Y. H5N1 influenza viruses: outbreaks and biological properties. Cell Res. 2010;20(1):51-61. [CrossRef]
 
Pandemic (H1N1) 2009-update 109. World Health Organization website. http://www.who.int/csr/don/2010_07_16/en/index.html. Accessed January 13, 2014.
 
Estenssoro E, Ríos FG, Apezteguía C, et al; Registry of the Argentinian Society of Intensive Care SATI. Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation. Am J Respir Crit Care Med. 2010;182(1):41-48. [CrossRef]
 
Vaillant L, La Ruche G, Tarantola A, Barboza P; Epidemic Intelligence Team at InVS. Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveill. 2009;14(33):pii 19309.
 
Centers for Disease Control and Prevention (CDC). Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR Morb Mortal Wkly Rep. 2009;58(27):749-752.
 
Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE, Fanning TG. Initial genetic characterization of the 1918 “Spanish” influenza virus. Science. 1997;275(5307):1793-1796. [CrossRef]
 
Neumann G, Noda T, Kawaoka Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature. 2009;459(7249):931-939. [CrossRef]
 
Morgan OW, Bramley A, Fowlkes A, et al. Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1) disease. PLoS ONE. 2010;5(3):e9694. [CrossRef]
 
Tumpey TM, Basler CF, Aguilar PV, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. 2005;310(5745):77-80. [CrossRef]
 
To KKW, Zhou J, Song Y-Q, et al. Surfactant protein B gene polymorphism is associated with severe influenza. Chest. 2014;145(6):1237-1243.
 
Chen H, Wen X, To KKW, et al. Quasispecies of the D225G substitution in the hemagglutinin of pandemic influenza A(H1N1) 2009 virus from patients with severe disease in Hong Kong, China. J Infect Dis. 2010;201(10):1517-1521. [CrossRef]
 
Jeffery CJ. Moonlighting proteins—an update. Mol Biosyst. 2009;5(4):345-350. [CrossRef]
 
Selman M, Lin H-M, Montaño M, et al. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Hum Genet. 2003;113(6):542-550. [CrossRef]
 
Baekvad-Hansen M, Dahl M, Tybjaerg-Hansen A, Nordestgaard BG. Surfactant protein-B 121ins2 heterozygosity, reduced pulmonary function, and chronic obstructive pulmonary disease in smokers. Am J Respir Crit Care Med. 2010;181(1):17-20. [CrossRef]
 
Atochina-Vasserman EN, Beers MF, Gow AJ. Review: chemical and structural modifications of pulmonary collectins and their functional consequences. Innate Immun. 2010;16(3):175-182. [CrossRef]
 
Abecasis GR, Altshuler D, Auton A, et al. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061-1073. [CrossRef]
 
Dushianthan A, Cusack R, Goss V, Postle AD, Grocott MP. Clinical review: Exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome - where do we go from here? Crit Care. 2012;16(6):238. [CrossRef]
 
Cox DR, Donnelly CA. Principles of Applied Statistics.1st ed. Cambridge, England: Cambridge University Press; 2011.
 

Figures

Tables

References

Neumann G, Chen H, Gao GF, Shu Y, Kawaoka Y. H5N1 influenza viruses: outbreaks and biological properties. Cell Res. 2010;20(1):51-61. [CrossRef]
 
Pandemic (H1N1) 2009-update 109. World Health Organization website. http://www.who.int/csr/don/2010_07_16/en/index.html. Accessed January 13, 2014.
 
Estenssoro E, Ríos FG, Apezteguía C, et al; Registry of the Argentinian Society of Intensive Care SATI. Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation. Am J Respir Crit Care Med. 2010;182(1):41-48. [CrossRef]
 
Vaillant L, La Ruche G, Tarantola A, Barboza P; Epidemic Intelligence Team at InVS. Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveill. 2009;14(33):pii 19309.
 
Centers for Disease Control and Prevention (CDC). Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR Morb Mortal Wkly Rep. 2009;58(27):749-752.
 
Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE, Fanning TG. Initial genetic characterization of the 1918 “Spanish” influenza virus. Science. 1997;275(5307):1793-1796. [CrossRef]
 
Neumann G, Noda T, Kawaoka Y. Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature. 2009;459(7249):931-939. [CrossRef]
 
Morgan OW, Bramley A, Fowlkes A, et al. Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1) disease. PLoS ONE. 2010;5(3):e9694. [CrossRef]
 
Tumpey TM, Basler CF, Aguilar PV, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. 2005;310(5745):77-80. [CrossRef]
 
To KKW, Zhou J, Song Y-Q, et al. Surfactant protein B gene polymorphism is associated with severe influenza. Chest. 2014;145(6):1237-1243.
 
Chen H, Wen X, To KKW, et al. Quasispecies of the D225G substitution in the hemagglutinin of pandemic influenza A(H1N1) 2009 virus from patients with severe disease in Hong Kong, China. J Infect Dis. 2010;201(10):1517-1521. [CrossRef]
 
Jeffery CJ. Moonlighting proteins—an update. Mol Biosyst. 2009;5(4):345-350. [CrossRef]
 
Selman M, Lin H-M, Montaño M, et al. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Hum Genet. 2003;113(6):542-550. [CrossRef]
 
Baekvad-Hansen M, Dahl M, Tybjaerg-Hansen A, Nordestgaard BG. Surfactant protein-B 121ins2 heterozygosity, reduced pulmonary function, and chronic obstructive pulmonary disease in smokers. Am J Respir Crit Care Med. 2010;181(1):17-20. [CrossRef]
 
Atochina-Vasserman EN, Beers MF, Gow AJ. Review: chemical and structural modifications of pulmonary collectins and their functional consequences. Innate Immun. 2010;16(3):175-182. [CrossRef]
 
Abecasis GR, Altshuler D, Auton A, et al. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061-1073. [CrossRef]
 
Dushianthan A, Cusack R, Goss V, Postle AD, Grocott MP. Clinical review: Exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome - where do we go from here? Crit Care. 2012;16(6):238. [CrossRef]
 
Cox DR, Donnelly CA. Principles of Applied Statistics.1st ed. Cambridge, England: Cambridge University Press; 2011.
 
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