Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Pharmacogenomics J. Author manuscript; available in PMC 2010 April 28.
Published in final edited form as:
PMCID: PMC2860600

Ethical considerations in the collection of genetic data from critically ill patients: What do published studies reveal about potential directions for empirical ethics research?


Critical illness trials involving genetic data collection are increasingly commonplace and pose challenges not encountered in less acute settings, related in part to the precipitous, severe and incapacitating nature of the diseases involved. We performed a systematic literature review to understand the nature of such studies conducted to date, and to consider, from an ethical perspective, potential barriers to future investigations. We identified 79 trials enrolling 24 499 subjects. Median (interquartile range) number of participants per study was 263 (116.75–430.75). Of these individuals, 16 269 (66.4%) were Caucasian, 1327 (5.4%) were African American, 1707 (7.0%) were Asian Pacific Islanders and 139 (0.6%) were Latino. For 5020 participants (20.5%), ethnicity was not reported. Forty-eight studies (60.8%) recruited subjects from single centers and all studies examined a relatively small number of genetic markers. Technological advances have rendered it feasible to conduct clinical studies using high-density genome-wide scanning. It will be necessary for future critical illness trials using these approaches to be of greater scope and complexity than those so far reported. Empirical research into issues related to greater ethnic inclusivity, accuracy of substituted judgment and specimen stewardship may be essential for enabling the conduct of such trials.

Keywords: critical illness, sepsis, organ failure, ethics, genetics, substituted judgment


Genetic variation influences disease predisposition and severity as well as treatment response.14 The use of genetic information to aid diagnosis, stratify risk and guide therapy has potential to impact most facets of medical practice, including care of critically ill patients.1,2,5 Substantial public and private investment has produced both more complete understanding of genomic structure and variation, and refinement in techniques to facilitate acquisition and analysis of genetic data.6 As a result, genetic information is increasingly collected both as part of epidemiological studies to delineate genotypic–phenotypic relationships, and as an adjunct to therapeutic trials.7 As in most sectors of medicine, there is substantial interest in applying genomic techniques to the study of critically ill patients.5

Collection of genetic material from the acutely ill poses logistical and ethical challenges not encountered in non-urgent settings. Conditions prompting intensive care unit admission are frequently precipitous and life threatening, and the care provided is highly technological. Neither patients nor family members have typically had the opportunity for education regarding the nature of the disease process, expected outcome, treatment alternatives or research opportunities. Furthermore, patients in intensive care units are frequently incapacitated and unable to provide informed consent permitting medical intervention or research participation.812 Finally, many therapies, such as for sepsis, myocardial infarction or stroke, must be administered quickly after diagnosis.10 If critically ill patients are to be enrolled in studies in which genetic material is collected, permission must often be obtained in a timely manner from surrogates (for example, family members, guardians or domestic partners), many of whom are being confronted with complex and serious medical issues for the first time. How the exigencies of acute illness affect perceptions of genetic data collection among patients, surrogates, clinicians and oversight bodies is largely unstudied.13,14

This commentary focuses on ethical considerations associated with the collection of genetic material from critically ill adults enrolled in clinical investigations. It is reasonable to question the extent to which such investigations occur. Although the ethical aspects of such studies would be identical whether rarely or commonly conducted, these issues might be viewed as esoteric or nugatory by oversight bodies and other stakeholders if such studies are infrequent, but a pressing policy concern if commonplace. Analogous to systematic literature reviews performed to evaluate methodological issues pertaining to the conduct of genetic epidemiology studies in critical illness,15 we performed a review to quantify the frequency of such studies, and to provide background for discussion of the ethical and social challenges such investigations pose.

Materials and methods

We performed a systematic review of clinical investigations involving collection of genetic data in the related clinical conditions of sepsis, septic shock and/or organ failure. We limited our review to studies of these conditions because we felt that this subgroup was sufficiently representative of all critical illness genetic studies in terms of trial characteristics and ethical issues posed to allow meaningful inference. Studies for potential inclusion were identified through a Medline search (English language, human, 1996–2007) using the terms `sepsis,' `septic shock,' `organ failure' and `organ dysfunction' as key words or subject headings. Related subject headings identified by these terms were also used. The subset of studies potentially involving genetic data collection was identified by selecting those studies also using `genetics,' `polymorphism,' `variant' and combinations of these terms as subject headings or key words. Related subject headings identified by these terms were used. Bibliographies of review articles retrieved by this search strategy were examined to identify additional relevant citations. Two of the authors (BDF, CRK) reviewed the abstracts of all manuscripts identified by this strategy, included those that were clinical studies in which genetic material was obtained from critically ill adults (age≥18 years), and extracted the following information: genetic variant studied, clinical entity studied, study location, whether study was single or multi-institutional, number of participants and ethnicity of participants. Several citations described the same study population, which we accounted for in the total number of subjects reported as well as their ethnic composition. This study was approved by the Human Research Protection Office of Washington University School of Medicine.


Our search parameters identified 79 studies enrolling 24 499 subjects reported over the 11-year period (1996–2007).1692 (Figure 1, Table 1). The median (interquartile range) of subjects reported in each study was 263 (116.75–430.75). Of these individuals, 16 269 (66.4%) were Caucasian, 1327 (5.4%) were African American, 1707 (7.0%) were Asian Pacific Islanders and 139 (0.6%) were Latino. For 5020 participants (20.5%), ethnicity was not reported. Thirty-seven studies (46.8% enrolling 12 409 patients) were conducted solely or partly in the United States,18,20,22,28,3640,42,45,47,50,52,53,55,56,58,6063,6770,72,75,77,81,82,87,9092,94,95 34 studies (43.0% enrolling 10 096 patients) were conducted exclusively or partly in Europe,16,19,2327,2935,43,44,46,48,49,54,57,59,65,66,73,74,78,80,8386,89,93 and the remainder were conducted in Asia, South America or Australia.17,41,51,64,71,76,79,88 Forty-eight studies (60.8%) recruited subjects from single centers,17,18,22,24,26,27,29,31,3342,44,47,50,52,53,5558,60,61, 63,64,70,71,73,7577,8089,92 16 (20.2%) were multicenter,16,20,21,25,28,30,32,43,46,54,59,67,69,90,91,94 with the remainder not specifying the number of participating centers.19,23,45,48,49,51,62,65,66,68,72,74,78,79,93 All studies examined a relatively small number of genetic markers; none used genome-wide scanning techniques.

Figure 1
Studies performed in sepsis involving collection of genetic material (1996–2007). (a) Bar graph representing number of patients reported each year in studies performed examining genetic influences related to sepsis, severe infection or organ failure. ...
Table 1
Studies in patients with sepsis, septic shock or organ failure involving collection of genetic data


Genetic information is often perceived as exceptional, associated with risks and requiring protections distinct from other types of data.96,97 Reasons underlying genetic exceptionalism include the possibility that genetic information is predictive and might re-categorize an individual from healthy to at-risk of disease, infer information about family members or produce emotional duress.96,98101 These perceptions may underlie the findings that individuals from many backgrounds—the general population, patients at-risk for hereditable disease and clinicians practicing in ambulatory settings—have expressed reluctance to permit collection of genetic information.102104 The manner in which the exigencies of acute illness might influence such perceptions is poorly understood.13 One of the most visible aspects of the debates pertaining to genetic exceptionalism focus on economic discrimination.103,105 The recently enacted Genetic Information Non-discrimination Act (GINA) may mitigate many of these concerns.106 GINA prohibits the use of genetic information by health insurers to determine eligibility or premiums, and by businesses for employment decisions (hiring, termination and so on). Although GINA's provisions extend to genetic data obtained through clinical investigation, they are not all encompassing. For example, GINA does not proscribe the use of genetic data to determine eligibility for life, disability or long-term care insurance, nor does it affect underwriting based on current health status.

Concern about the potential exceptional nature of genetic data is mirrored in Institutional Review Board behavior. Institutional Review Board's affiliated with participating venues for multicenter genetic studies vary both in their view of the risks such studies pose, and the protections put in place.7,107 Such variability is problematic. Recruitment of individuals to participate in genetic data collection at some sites but not others, or having differing consenting standards and processes in place at participating institutions, would be expected to introduce sampling bias. Our analysis of critical illness investigations suggests that the minority of these studies to date have been multicenter. Thus, while investigators conducting clinical research in which genetic material is collected may not have dealt with issues related to variable Institutional Review Board behavior to date, this issue is expected to gain relevance, as has been described for non-genetic studies in critical illness.108

Do racial or ethnic barriers to the collection of genetic material exist?

For studies using genetic data collection to be maximally informative, they must be ethnically and racially inclusive.109,110 Our examination of studies conducted in acute illness suggests underrepresentation (and/or underreporting) of ethnic minority groups. The ethnic makeup of those studies wholly or partly performed in the United States (11 447 participants) was 74.0% Caucasian, 11.6% African American, 1.2% Hispanic-Latino and 0.1% Asian Pacific Islanders. For 13.0% of enrollees, ethnicity was not described. We do not know if this ethnic composition differs from that of studies conducted in similar populations in which genetic data was not collected or from the composition of the populations from which these patients were recruited. Nonetheless, the ethnic composition of participants seems to differ significantly from that of the US population ( On the basis of the current census data, African Americans, Latino-Hispanics and Asian Pacific Islanders comprise 12.9, 12.5 and 4.2% of the US population, respectively, with each of these constituencies experiencing rapid growth ( The Latino-Hispanic population alone expanded 57.9% between 1990 and 2000 (

Low rates of participation of ethnic minority populations in clinical research is well documented and is described for studies involving collection of genetic data conducted in non-acutely ill individuals.111116 Fifty-eight percent of African–American respondents expressed a willingness to participate in a hypothetical study examining the genetic basis of tobacco addiction.117 Similarly, African Americans were less likely than other ethnic groups to permit collection of genetic data as part of longitudinal studies examining health and nutritional status118 and type 2 diabetes.7 Several investigators have reported that relative to Caucasians, African Americans were more likely to believe that collection of genetic data would have negative ramifications.119121 The manner in which incorporation of genotyping might influence such perceptions, and possibly further hinder research participation in the context of critical illness, is unstudied. Attention to recruitment of diverse populations for clinical investigation is essential not only for understanding genomic influences on health and disease, but also for ultimately applying the knowledge created by these studies to all segments of society.

What concerns exist regarding future potential uses of genetic data?

We found that investigations involving patients with sepsis were generally of moderate size and involved study of a limited number of genetic loci. With the advent of techniques enabling genome-wide scanning, studies enrolling several thousand patients are needed to sufficiently characterize genotypic–phenotypic relationships.122 Such studies have been conducted in the setting of non-acute illness.123126 Very large biobanks have been established to enable investigations of this scale.127,128 Conducting comparable studies in the setting of acute illness will likely become common.

The use of biobanks and tissue repositories leads to questions regarding consent to permit future use of this material. The willingness of patients to allow their genetic data to be used for unspecified future studies is unknown in most contexts—including critical illness—and raises ethical and policy concerns. An expedient solution is to obtain comprehensive consent for any and all future unspecified research at time of specimen acquisition.129 Helft et al. surveyed oncology patients who had contributed samples to a biobank using such a consent mechanism.130 When presented with specific research scenarios, these donors expressed clear boundaries for use.130 For example, a significant minority of respondents did not wish other research institutions, drug companies or for-profit entities to have access to their samples. More than one-third of the respondents were concerned about privacy and expressed a strong preference for sample de-identification. Compared with other ethnic groups, African Americans were less likely to permit future use for several indications. These findings illustrate an inherent limitation of blanket consent; subjects cannot be given sufficient information about the risks of a future undefined study so as to make an informed choice.

Several approaches have been proposed to obviate these concerns, including requiring donor re-contact for all future sample use, sample de-identification with the intent of carrying out future research without need for re-contact and use of tiered consents, that is, specifying the types of applications the samples might be used for and obtaining consent for specific levels of research.129 As noted below, how these approaches might be implemented in the context of critical illness remains a challenge.

Considerations in obtaining informed consent

Obtaining informed consent in the context of critical illness genetic studies pose challenges. Although permission to participate in clinical research in such settings is generally obtained from surrogates, available evidence suggests that the concordance between these proxy decision makers and the patients represented is poor.810,131137

There is precedence for waiver of informed consent in investigations of emergency conditions under select circumstances ((21CFR50.24) Exception from informed consent requirements for emergency research). Specifically, the condition under study must be life-threatening and available treatments unsatisfactory. Furthermore, the urgency of the situation and the patient's incapacitation render it impractical to obtain informed consent from either the potential participant themselves or their surrogate. Such circumstances would rarely apply to studies involving collection of genetic data performed in the intensive care unit. The dilemma becomes whether to rely solely on patient's surrogate for consent, to obtain consent from the patient once their critical illness has abated or possibly a hybrid of these approaches. While for selected investigations, it would be appropriate to obtain participants' consent following recovery, and not rely on surrogate judgment, there exist practical limitations to this approach. For genetic epidemiology studies, subjects who either expire or who are lost to follow-up would not be enrolled, potentially eliminating an informative subset of genetic variants from analysis. Furthermore, such studies are dependent upon a robust clinical database to define genotypic–phenotypic relationships. Construction of such a database is ideally real-time and prospective. Collecting this data retrospectively, after a patient has recovered and provided consent, would likely be less accurate and detailed. Similarly, discarding prospectively collected data because a patient declines to participate would strain limited resources. Finally, a research design dependent upon gaining informed consent from patients once they have regained decision-making capacity would effectively preclude trials that base critical care therapy on individual genotype. Ultimately, the investigator is reliant upon the patient's surrogate to provide consent.

We are not suggesting that empirical investigation will negate or supplant the obligation to determine patient's wishes once incapacitation from acute illness abates. Furthermore, many aspects of genetic research, such as donor re-contact to delineate future sample use, would appear most appropriately addressed to the recovered patient. Nonetheless, gaining a fuller understanding of attitudes of surrogates regarding genetic data collection and of the accuracy with which these views reflect those of the patients represented potentially allows critical illness investigations to proceed in an ethically rigorous and resource sensitive manner.


A limitation of our analysis is that we examined a narrow focus of acute illness, specifically sepsis and acute organ dysfunction. Some of our observations, such as those pertaining to ethnic representation, enrollment size and multicenter participation, might not be generalizable to other applications in critical care such as myocardial infarction or stroke. In contrast, considerations related to the accuracy of substituted judgment and archiving and future use of genetic data are more likely to be broadly relevant to critical care investigations and illustrate the challenges in conducting these studies.


The ethical implications of critical illness genetics research are poorly studied. It might be argued that the most `conservative' ethical approach in this setting would be the use of research designs based exclusively on anonymized data sets. Although such investigations would be of undeniable value, they would have limitations. Specifically, studies based on anonymized data collection would preclude assessment of long-term (for example, post-hospitalization) outcomes and would constrain future analyses of archived samples. Obtaining maximal impact of critical illness investigation will require that the scientific community have access to non-anonymized data. Empirical research to more fully understand the views of patients and their surrogates regarding genetic data collection is necessary to guide investigators, oversight bodies and other stakeholders with a vested interest in conducting these investigations in the most ethically rigorous manner possible.


This research was supported in part by GM080591.


Conflict of interest

The authors declare no conflict of interest.


1. Collins FS. Shattuck lecture—medical and societal consequences of the human genome project. N Engl J Med. 1999;342:28–37. [PubMed]
2. Bell J. The new genetics in clinical practice. Br Med J. 1998;316:618–620. [PMC free article] [PubMed]
3. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487–491. [PubMed]
4. Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med. 2003;348:538–549. [PubMed]
5. Freeman BD, McLeod HL. Challenges of implementing pharmacogenetics in the critical care environment. Nat Rev Drug Discov. 2004;3:88–93. [PubMed]
6. Wadman M. James Watson's genome sequenced at high speed. Nature. 2008;452:788. [PubMed]
7. Espeland MA, Dotson K, Jaramillo SA, Kahn SE, Harrison B, Montez M, et al. Consent for genetics studies among clinical trial participants: findings from Action for Health in Diabetes (Look AHEAD) Clin Trials. 2006;3:456. [PMC free article] [PubMed]
8. Davis N, Pohlman A, Gehlbach B, Kress JP, McAtee J, Herlitz J, et al. Improving the process of informed consent in the critically ill. J Am Med Assoc. 2003;289:1963–1968. [PubMed]
9. Luce JM. Research ethics and consent in the intensive care unit. Curr Opin Crit Care. 2003;9:540–544. [PubMed]
10. Ad Hoc Statement Committee of the American Thoracic Society The ethical conduct of clinical research involving critically ill patients in the United States and Canada. Am J Respir Crit Care Med. 2004;170:1375–1384. [PubMed]
11. Luce JM. Is the concept of informed consent applicable to clinical research involving critically ill patients? Crit Care Med. 2003;31(3 Suppl):S153–S160. [PubMed]
12. Silverman HJ, Luce JM, Lanken PN, Morris AH, Harabin AL, Oldmixon CF, et al. Recommendations for informed consent forms for critical care clinical trials. Crit Care Med. 2005;33:867–882. [PubMed]
13. Freeman BD, Kennedy CR, Coopersmith CM, Zehnbauer BA, Buchman TG. Genetic testing and research in critical care: surrogates' perspective. Crit Care Med. 2006;34:986–994. [PubMed]
14. Lavery JV, Slutsky AS. Substitute decisions about genetic testing in critical care research: a glimpse behind the curtain. Crit Care Med. 2006;34:1257–1259. [PubMed]
15. Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006;32:1706–1712. [PubMed]
16. Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, et al. Association of TNF2, a TNF promoter polymorphism, with septic shock susceptibility and mortality—a multicenter study. J Am Med Assoc. 1999;282:561–568. [PubMed]
17. Tang G, Huang S, Yien H, Chen C, Wu CW, Chi C, et al. Tumor necrosis factor gene polymorphism and septic shock in surgical infection. Crit Care Med. 2000;28:2733–2736. [PubMed]
18. O'Keefe GE, Hybki DL, Munford RS. The G->a single nucleotide polymorphism at the −308 position in the tumor necrosis factor-[alpha] promoter increases the risk for severe sepsis after trauma. J Trauma. 2002;52:817–826. [PubMed]
19. Majetschak M, Obertacke U, Schade FU, Bardenheuer M, Voggenreiter G, Bloemeke B, et al. Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma. Clin Diagn Lab Immunol. 2002;9:1205–1211. [PMC free article] [PubMed]
20. Kerlin BA, Yan SB, Isermann BH, Brandt TJ, Sood R, Basson BR, et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood. 2003;102:3085–3092. [PubMed]
21. Yan SB, Nelson DR. Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C. Crit Care Med. 2004;32(Suppl):S239–S246. [PubMed]
22. Waterer GW, Quasney MW, Cantor RM, Wunderink RG. Septic shock and respiratory failure in community acquired pneumonia have different TNF polymorphism associations. Am J Respir Crit Care Med. 2001;163:1599–1604. [PubMed]
23. Schaaf BM, Boehmke F, Esnashaashari H, Seitzer U, Kothe H, Maas M, et al. Pneumococcal septic shock is associated with the IL-10-1082 gene promoter polymorphism. Am J Respir Crit Care Med. 2003;168:476–480. [PubMed]
24. Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;166:646–650. [PubMed]
25. Majetschak M, Flohe S, Obertacke U, Schroder J, Staubach K, Nast-Kob D, et al. Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg. 1999;230:207–214. [PubMed]
26. Stuber F, Peterson M, Bokelman F, Schade U. A genomic polymorphism in the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med. 1996;24:381–384. [PubMed]
27. Lowe PR, Galley HF, Ashraf AF, Webster NR. Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in patients with sepsis. Crit Care Med. 2003;31:34–38. [PubMed]
28. Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with Gram negative septic shock. Arch Inter Med. 2002;162:1028–1032. [PubMed]
29. Schroeder S, Reck M, Hoeft A, Stuber F. Analysis of two leukocyte antigen linked polymorphic heat shock protein 70 genes in patients with severe sepsis. Crit Care Med. 1999;27:1265–1270. [PubMed]
30. Gibot S, Cariou A, Drouet L, Rossignol M, Ripoll L. Association between a genomic polymorphism between the CD14 locus and septic shock susceptibility and mortality rate. Crit Care Med. 2002;30:969–973. [PubMed]
31. Garred P, Strom JJ, Quist L, Taaning E, Madsen HO. Association of mannose binding lectin polymorphisms with sepsis and fatal outcome in patients with systemic inflammatory response syndrome. J Infect Dis. 2003;188:1394–1403. [PubMed]
32. Hubacek JA, Stuber F, Frolich D, Book M, Wetegrove S, Roth G, et al. The common function C(−159)T polymorphism within the promoter region of the lipopolysaccharide receptor is not associated with sepsis development or mortality. Genes Immun. 2000;1:405–407. [PubMed]
33. Ma P, Chen D, Pan J, Du B. Genomic polymorphisms within the interleukin-1 family cytokines influences the outcome of septic patients. Crit Care Med. 2002;30:1046–1050. [PubMed]
34. Schluter B, Raufhake C, Erren M, Schotte H, Kippe F, Rust S, et al. Effect of the interleukin-6 promoter polymorphism (−174 G/C) gene on the incidence and outcome of sepsis. Crit Care Med. 2002;30:32–37. [PubMed]
35. Arnalich F, Lopez-Maderuelo D, Codoceo R, Lopez J, Solis-Gorrido LM, Capiscol C, et al. Interleukin-1 receptor antagonist gene polymorphism and mortality with patients in sepsis. Clin Exp Immunol. 2002;127:331. [PubMed]
36. Stassen NA, Leslie-Norflet LA, Robertson AM, Eichenberger MR, Polk HC. Interferon-gamma gene polymorphisms and the development of sepsis in patients with trauma. Surgery. 2002;132:289–292. [PubMed]
37. Davis EG, Eichenberger MR, Gran BS, Polk HC. Microsatellite marker of interferon gamma receptor 1 gene correlates with infection following major trauma. Surgery. 2000;128:301–305. [PubMed]
38. Barber RC, O'Keefe GE. Characterization of a single nucleotide polymorphism in the lipopolysaccharide binding protein and its association with sepsis. Am J Respir Crit Care Med. 2003;167:1316–1320. [PubMed]
39. Barber RC, Aragaki CC, Rivera-Chavez FA, Purdue GF, Hunt JL, Horton JW. TLR4 and TNF-alpha polymorphisms are associated with an increased risk of severe sepsis following burn injury. J Med Genet. 2004;41:808–813. [PMC free article] [PubMed]
40. Sutherland AM, Walley KR, Russell JA. Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults. Crit Care Med. 2005;33:638–644. [PubMed]
41. Watanabe E, Hirasawa H, Oda S, Matsuda K, Hatano M, Tokuhisa T. Extremely high interleukin-6 blood levels and outcome in the critically ill are associated with tumor necrosis factor- and interleukin-1-related gene polymorphisms. Crit Care Med. 2005;33:89–97. [PubMed]
42. Quasney MW, Waterer GW, Dahmer MK, Kron GK, Zhang Q, Kessler LA, et al. Association between surfactant protein B +1580 polymorphism and the risk of respiratory failure in adults with community acquired pneumonia. Crit Care Med. 2004;32:1115–1119. [PubMed]
43. Hubacek JA, Stuber F, Frolich D, Book M, Wetegrove S, Ritter M, et al. Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis. Crit Care Med. 2001;29:557–561. [PubMed]
44. Fang XM, Schroder S, Hoeft A, Stuber F. Comparison of two polymorphisms of the interleudin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med. 1999;27:1330–1334. [PubMed]
45. Quasney MW, Watere GW, Dahmer MK, Turner D, Zhang Q, Cantor RM. Intracellular adhesion molecule Gly241Arg polymorphism has no impact on ARDS or septic shock in community-acquired pneumonia. Chest. 2002;121(3 Suppl):85S–86S. [PubMed]
46. Gordon AC, Lagan AL, Aganna E, Cheung L, Peters CJ, McDermott MF, et al. TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immun. 2004;5:631–640. [PubMed]
47. Sutherland AM, Walley KR, Manodha S, Russell JA. The association of interleukin 6 haplotype clades with mortality in critically ill adults. Arch Inter Med. 2005;165:75–82. [PubMed]
48. Heesen M, Bloemeke B, Schade U, Obertacke U, Majetschak M. The −260 C to T promoter polymorphism of the lipopolysaccharide receptor CD14 and severe sepsis in trauma patients. Intensive Care Med. 2002;28:1161–1163. [PubMed]
49. Rauchschwalbe SK, Maseizik T, Mittelkotter U, Schluter B, Patzig C, Reith HB. Effect of the LT-alpha (+250G/A) polymorphism on markers of inflammation and clinical outcome in critically ill patients. J Trauma. 2004;56:815–822. [PubMed]
50. Stassen NA, Breit CM, Norfleet LA, Polk HC. IL-18 promoter polymorphisms correlate with the development of post-injury sepsis. Surgery. 2003;134:351–356. [PubMed]
51. Dianliang Z, Jieshou L, Zhiwei J, Baojun Y. Association of plasma levels of tumor necrosis factor (TNF)-alpha and its soluble receptors, two polymorphisms of the TNF gene, with acute severe pancreatitis and early septic shock due to it. Pancreas. 2003;26:339–343. [PubMed]
52. Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis. 2002;186:1522–1525. [PubMed]
53. Calvano JE, Um JY, Agnese DM, Hahm SJ, Kumar A, Coyle SM, et al. Influence of the TNF-alpha and TNF-beta polymorphisms upon infectious risk and outcome in surgical intensive care patients. Surg Infect. 2003;4:163–169. [PubMed]
54. Frerkling I, Sengler C, Gunther A, Walmrath H, Stevens P, Witt H, et al. Evaluation of the −26G>A CC16 polymorphism in the acute respiratory distress syndrome. Crit Care Med. 2005;33:2404–2406. [PubMed]
55. Lin Z, Pearson C, Chinchilli V, Pietschmann SM, Luo J, Pison U, et al. Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS. Clin Genet. 2000;59:181–191. [PubMed]
56. Moretti EW, Morris RW, Podgoreanu M, Schwinn DA, Newman MF, Bennett E, et al. APOE polymorphism is associated with risk of severe sepsis in surgical patients. Crit Care Med. 2005;33:2521–2526. [PubMed]
57. Gong MN, Wei Z, Xu L, Miller DP, Thompson BT, Christiani DC. Polymorphisms in the surfactant protein-B gene, gender, and the risk of direct pulmonary injury and ARDS. Chest. 2004;125:211. [PubMed]
58. Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Boyce P, et al. 308GA and TNFB polymorphisms in acute respiratory distress syndrome. Eur Respir J. 2005;26:382–389. [PubMed]
59. Gordon AC, Waheed U, Hansen TK, Hitman GA, Garrard CS, Turner MW, et al. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock. 2006;25:88–93. [PubMed]
60. Gong MN, Zhou W, Williams PL, Thompson T, Pothier L, Christiani DC. Polymorphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome. Crit Care Med. 2007;35:48–56. [PMC free article] [PubMed]
61. Gong MN, Thompson BT, Williams PL, Zhou W, Wang MZ, Pothier L, et al. Interleukin-10 polymorphism in position-1082 and acute respiratory distress syndrome. Eur Respir J. 2006;27:674–681. [PMC free article] [PubMed]
62. Arcaroli J, Silva E, Maloney JP, He Q, Svetkauskaite D, Murphy JR, et al. Variant IRAK-1 haplotype is associated with increased nuclear factor-kB activation and worse outcomes in sepsis. Am J Respir Crit Care Med. 2008;173:1335–1341. [PMC free article] [PubMed]
63. Boudoin SV, Saunders D, Tiangyou W, Elson JL, Poynter J, Pyle A, et al. Mitochondrial DNA and survival after sepsis: a prospective study. Lancet. 2008;366:2118–2121. [PubMed]
64. D'Avila L, Albarus MH, Franco CR, Aguiar BB, Oliveira JR, Dias FS, et al. Effect of CD14-260C>T polymorphism on the mortality of critically ill patients. Immunol Cell Biol. 2006;84:342–348. [PubMed]
65. Eklund C, Huttunen R, Syrjanen J, Laine J, Vuento R, Hurme M. Polymorphism of the c-reactive protein gene is associated with mortality in bacteremia. Scand J Infect Dis. 2006;38:1069–1073. [PubMed]
66. Flores C, Maca-Meyer N, Perez-Mendez L, Sanguesa R, Espinosa E, Muriel A, et al. A CXCL2 tandem repeat promoter polymorphism is associated with susceptibility to severe sepsis in the Spanish population. Genes Immun. 2008;7:141–149. [PubMed]
67. Gao L, Grant A, Halder I, Brower R, Sevransky J, Maloney JP, et al. Novel polymorphisms in the myosin light chain kinase gene confer risk of acute lung injury. Am J Respir Cell Mol Biol. 2006;34:487–495. [PMC free article] [PubMed]
68. Garcia J, Vinasco LM. Genomic insights into acute inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2006;291:L1113–L1117. [PubMed]
69. Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun. 2000;68:6398–6401. [PMC free article] [PubMed]
70. Garnacho-Montero J, Aldabo-Pallas T, Garnacho-Montero C, Cayuela A, Jimenez R, Barroso S, et al. Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis. Crit Care. 2006;10:R111. [PMC free article] [PubMed]
71. Nakada T, Hirasawa H, Oda S, Shiga H, Matsuda K, Nakamura M, et al. Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukin-10 gene polymorphisms on clinical outcome in Japanese critically ill patients. J Surg Res. 2005;129:322–328. [PubMed]
72. Nonas S, Finigan J, Gao L, Garcia J. Functional genomic insights into acute lung injury: role of ventilators and mechanical stress. Proc Am Thoracic Soc. 2005;2:188–194. [PubMed]
73. O'Dwyer M, Dempsey F, Crowley V, Kelleher D, McManus R, Ryan T. Septic shock is correlated with asymmetrical dimethyl arginine levels, which may be influenced by a polymorphism in the dimethylarginine dimethylaminohydrolase II gene: a prospective observational study. Crit Care. 2006;10:R139. [PMC free article] [PubMed]
74. Riese J, Woerner K, Zimmermann P, Denzel C, Hohenberger W, Haupt W. Association of a TNF-β gene polymorphism with complications after major abdominal operations. Shock. 2003;19:1–4. [PubMed]
75. Walley KR, Russell JA. Protein C-1641AA is associated with decreased survival and more organ dysfunction in severe sepsis. Crit Care Med. 2007;35:12–17. [PubMed]
76. Watanabe E, Hirasawa H, Oda S, Shiga H, Matsuda K, Nakamura M, et al. Cytokine-related genotypic differences in peak interleukin-6 blood levels of patients with SIRS and septic complications. J Trauma. 2005;59:1181–1190. [PubMed]
77. Wattanathum A, Manocha S, Groshaus H, Russell JA, Walley KR. Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis. Chest. 2005;128:1690–1698. [PubMed]
78. Zhang D, Li J, Jiang Z, Yu B, Tang X. Association of two polymorphisms of tumor necrosis factor gene with acute severe pancreatitis. J Surg Res. 2003;112:138–143. [PubMed]
79. Zhang D, Zheng H, Yu B, Jiang Z, Li J. Association of polymorphisms of IL and CD14 genes with acute severe pancreatitis and septic chock. World J Gastroenterol. 2005;11:4409–4413. [PubMed]
80. Appoloni O, Dupont E, Vandercruys M, Andriens M, Duchateau J, Vincent JL. Association of tumor necrosis factor-2 allele with plasma tumor necrosis factor-alpha levels and mortality from septic shock. Am J Med. 2001;110:486–488. [PubMed]
81. Barber RC, Chang LE, Arnoldo BD, Purdue GF, Hunt JL, Horton JW, et al. Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res. 2006;4:250–255. [PubMed]
82. Barber RC, Aragaki CC, Chang LE, Purdue GF, Hunt JL, Arnoldo BD, et al. CD14-159 C Allele is associated with increased risk of mortality after burn injury. Shock. 2007;27:232–237. [PubMed]
83. Domingo P, Muniz-Diaz E, Baraldes MA, Arilla M, Barquet N, Pericas R, et al. Associations between Fc-gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease. Am J Med. 2002;112:19–25. [PubMed]
84. Flach R, Majetschak M, Heukamp T, Jennissen V, Flhe S, Borgermann J, et al. Relation of ex vivo stimulated blood cytokine synthesis to post-traumatic sepsis. Cytokine. 2008;11:173–178. [PubMed]
85. Reid CL, Perrey C, Pravica V, Hutchinson IV, Campbell LT. Genetic variation in pro-inflammatory and anti-inflammatory cytokine production in multiple organ dysfunction syndrome. Crit Care Med. 2002;30:2216–2221. [PubMed]
86. Schroder O, Schulte KM, Ostermann P, Roher HD, Ekkemkamp A, Laun RA. Heat shock protein 70 genotypes HSPa1B and HSPA1L influence cytokine concentrations and interfere with outcome after injury. Crit Care Med. 2003;31:73–79. [PubMed]
87. Spolarics Z, Siddiqui M, Siegel JH, Carcia ZC, Stein DS, Ong H, et al. Increased incidence of sepsis and altered monocyte functions in severely injured type A-glucose-6-phosphate dehydrogenase deficient African American trauma patients. Crit Care Med. 2001;29:728–736. [PubMed]
88. Eisen DP, Dean MM, Thomas P, Marshall P, Gerns N, Heatley S, et al. Low mannose-binding lectin function is associated with sepsis in adult patients. FEMS Immunol Med Microbiol. 2006;48:274–282. [PubMed]
89. Garcia-Segarra G, Epinosa G, Tassies D, Oreola J, Aibar J, Bove A, et al. Increased mortality in septic shock with the 4G/4G genotype of plasminogen activator inhibitor 1 in patients of white descent. Intensive Care Med. 2007;33:1354–1362. [PubMed]
90. Jaber BL, Rao M, Guo D, Balakrishnan VS, Perianayagam MC, Freeman RB, et al. Cytokine gene promoter polymorphisms and mortality in acute renal failure. Cytokine. 2004;25:212–219. [PubMed]
91. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis. Arch Inter Med. 2008;167:1655–1663. [PubMed]
92. Silva E, Arcaroli J, Svetkauskaite D, Coldren C, Nick JA, pocj K, et al. HMGB1 and LPS induce distinct patterns of gene expression and activation in neutrophils from patients with sepsis-induced acute lung injury. Intensive Care Med. 2007;33:1829–1839. [PubMed]
93. Menges T, Hermans PWM, Little SG, Langefeld T, Bonig O, Engel J, et al. Plasminogen activator inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet. 2001;357:1096–1097. [PubMed]
94. Saleh M, Viallancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature. 2004;429:75–79. [PubMed]
95. Curfman GD, Morrissey S, Drazen JM, et al. Expression of concern: Bombardier. N Engl J Med. 2005;353:2813–2814. `Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis' N Engl J Med 2000;343:1520-8. [PubMed]
96. Green MJ, Boytkin JR. `Genetic exceptionalism' in medicine: clarifying the differences between genetic and non-genetic tests. Ann Inter Med. 2003;138:571–575. [PubMed]
97. Lin Z, Owen AB, Altman RB. Genomic research and human subject privacy. Science. 2004;305:183. [PubMed]
98. Secretary's Advisory Committee on Genetics, Health, and Society . A roadmap for the integration of genetics and genomics into health and society. 2004. pp. 1–62.
99. Geller G, Botkin JR, Green MJ, Press N, Biesecker BB, Wilfond B, et al. Genetic testing for susceptibility to adult-onset cancer: the process and content of informed consent. J Am Med Assoc. 1997;277:1467–1474. [PubMed]
100. Kodish ED. Testing children for cancer genes: the rule of earliest onset. J Pediatrics. 1999;135:390–395. [PubMed]
101. Nelson RM, Botkin JR, Kodish ED, Levetown M, Truman JT, Wilfond BS. Ethical issues with genetic testing in pediatrics. Pediatrics. 2001;107:1451–1455. [PubMed]
102. Rothstein MA, Hornung CA. Public attitudes about pharmacogenomics. In: Rothstein MA, editor. Pharmacogenomics: Social, Ethical, and Clinical Dimensions. Wiley-Liss; Hoboken: 2003. pp. 3–27.
103. Lapham EV, Kozma C, Weiss JO. Genetic discrimination: perspectives of consumers. Science. 1996;274:3015–3021. [PubMed]
104. Freedman AN, Wideroff L, Olson L, Davis W, Klabunde C, Srinath KP, et al. US physicians' attitudes towards testing for cancer susceptibility. Am J Med Genet. 2003;120A:63–71. [PubMed]
105. Clayton EW. Ethical, legal, and social implications of genomic medicine. N Engl J Med. 2003;349:562–569. [PubMed]
106. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings and withdrawals for prescription medications. J Am Med Assoc. 2002;287:2215–2220. [PubMed]
107. McWilliams R, Hoover-Fong J, Hamosh A, Beck S, Beaty T, Cutting G. Problematic variation in local institutional review of a multicenter genetic epidemiology study. J Am Med Assoc. 2003;290:360–366. [PubMed]
108. Silverman H, Chandros S, Sugarman J. Variability among institutional review boards' decisions within the context of a multicenter trial. Crit Care Med. 2001;29:235–241. [PubMed]
109. Terwilliger JD, Weiss KM. Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr Opin Biol. 1998;9:578–594. [PubMed]
110. Terwilliger JD, Haghighi F, Hiekkalinna TS, Goring HHH. A biased assessment of the use of SNPs in human complex traits. Curr Opin Genet Develop. 2002;12:726–734. [PubMed]
111. Institute of Medicine . Unequal treatment: confronting racial and ethnic disparities in health care. The National Academies Press; Washington, DC, USA: 2002. [PMC free article] [PubMed]
112. Corbie-Smith G, Thomas SB, St George DMM. Distrust, race and research. Arch Inter Med. 2002;162:2458–2463. [PubMed]
113. Murthy VH, Krumhoz HM, Gross CP. Participation in cancer clinical trials. Race-, sex-, and age-based disparities. J Am Med Assoc. 2004;291:2720–2726. [PubMed]
114. Corbie-Smith G, Thomas SB, Williams MV, Moody-Ayers S. Attitudes and beliefs of African Americans toward participation in medical research. J Gen Inter Med. 1999;14:537–546. [PMC free article] [PubMed]
115. Shavers VL, Lynch CF, Burmeister LF. Racial differences in factors that influence the willingness to participate in medical research studies. Ann Epidemiol. 2005;12:248–256. [PubMed]
116. Simon CM, Kodish ED. Step into my zapatos, doc. Understanding and reducing communication disparities in the multicultural informed consent setting. Perspect Biol Med. 2005;48(1 (Supplement):S123–S138. [PubMed]
117. Halbert CH, Gandy OH, Collier A, Shaker L. Intentions to participate in genetics research among African American smokers. Cancer Epidemiol Biomarkers Prev. 2006;15:150–153. [PubMed]
118. McQuillan GM, Porter KS, Agelli M, Kington R. Consent for genetic research in a general population: the NHANES experience. Genet Med. 2003;5:35–42. [PubMed]
119. Furr LA. Perceptions of genetics research as harmful to society: differences among samples of African Americans and European-Americans. Genet Test. 2002;6:25–30. [PubMed]
120. Singer E, Antonuuci T, Van Hoewyk J. Similar results were found in a national survey of attitudes about genetic testing in which African Americans also reported significantly greater concerns about the negative consequences of genetic testing compared with Caucasians. Genet Test. 2004;8:31–43. [PubMed]
121. Thompson HS, Valdimarsdottir HB, Jandorf L, Redd W. Perceived disadvantages and concerns about abuses of genetic testing for cancer risk: differences across African American, Latina and Caucasian women. Patient Educ Couns. 2003;51:217–227. [PubMed]
122. Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005;6:95–98. [PubMed]
123. The Wellcome Trust Case Control Consortium Genome-wide association study of 14 000 cases of seven common disease and 3000 shared controls. Nature. 2007;447:661–678. [PMC free article] [PubMed]
124. Diabetes Genetics Initiative of Broad Institute of Harvard and MIT LUaNIoBR Genome wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316:1331–1336. [PubMed]
125. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, et al. Replication of genome-wide association signals in UK samples reveals risk loci for Type 2 diabetes. Science. 2007;316:1336–1341. [PMC free article] [PubMed]
126. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316:1488–1491. [PMC free article] [PubMed]
127. Ollier W, Sprosen T, Peakman T. UK Biobank: from concept to reality. Pharmacogenomics. 2005;6:639–646. [PubMed]
128. Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR, et al. Development of a large-scale de-identified DNA biobank to enable personalize medicine. Clin Pharmacol Ther. 2008;84:362–369. [PMC free article] [PubMed]
129. McGuire AL, Gibbs RA. No longer de-identified. Science. 2006;312:370–371. [PubMed]
130. Helft PR, Champion VL, Eckles R, Johnson CS, Meslin EM. Cancer patients' attitudes toward future research uses of stored human biological materials. J Emp Res Human Res Ethics. 2007;2:15–22. [PubMed]
131. Fost N. Can acutely ill patients consent to research? Resolving an ethical dilemma with facts. Acad Emerg Med. 1999;6:772–774. [PubMed]
132. Sulmasy DP, Terry PB, Weisman CS, Miller DJ, Stallings RY, Vettese MA, et al. The accuracy of substituted judgments in patients with terminal diagnoses. Ann Intern Med. 1998;128:621–629. [PubMed]
133. Hare J, Pratt C, Nelson C. Agreement between patients and their self-selected surrogates on difficult medical decisions. Arch Intern Med. 1992;152:1049–1054. [PubMed]
134. Seckler AB, Meier DE, Mulvihill M, Paris BE. Substituted judgment: how accurate are the predictions? Ann Intern Med. 1991;115:92–98. [PubMed]
135. Sulmasy DP, Haller K, Terry PB. More talk, less paper: predicting the accuracy of substituted judgments. Am J Med. 1994;96:432–438. [PubMed]
136. Coppolino M, Ackerson L. Do surrogate decision makers provide accurate consent for intensive care research? Chest. 2001;119:603–612. [PubMed]
137. Suhl J, Simons P, Reedy T, Garrick T. Myth of substituted judgment: Surrogate decision making regarding life support is unreliable. Arch Intern Med. 1994;154:90–96. [PubMed]