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Major Concerns About Study Design and Clinical Biomarker Interpretation

Published:November 25, 2013DOI:https://doi.org/10.1016/j.amjmed.2013.10.025
      To the Editor:
      We are writing this letter in response to the recent article in The American Journal of Medicine by D'Andrea and Reddy.
      • D'Andrea M.A.
      • Reddy G.K.
      Health consequences among subjects involved in Gulf oil spill clean-up activities.
      Our primary concerns are with their convenience sampling and case-control mismatching, and the authors' conclusions about the clinical results. The clinical results indicate that both groups in their study, unexposed and exposed, have clinical biomarker values for both liver function and blood profiles that essentially fall within the normal ranges for healthy adult individuals (Table).

      National Library of Medicine. MedLine Plus. Available at: http://www.nlm.nih.gov/medlineplus/. Accessed September 18, 2013.

      Mayo Clinic. Available at: http://www.mayoclinic.com. Accessed September 18, 2013.

      Agency for Toxic Substances Disease Registry, Centers for Disease Control and Prevention. Available at: http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed September 18, 2013.

      Results from clinical laboratories tend to vary only slightly for such routine and standardized tests. Statistical differences among such unmatched groups do not necessarily equate to biologically meaningful differences. Their results should include an explicit reference and comparison to well-documented clinical ranges for normal, healthy adult individuals. An alternative conclusion about their clinical results is that while these age- and sex-biased convenience samples differ from one another statistically, neither group actually differs from accepted values for normal, healthy adult individuals. This equally valid conclusion might well serve to comfort the patients under evaluation in that, as individuals, none appear to have any clinical indications of abnormal liver or hematological function. We hold that this should have been explicitly discussed, and we are concerned that the conclusion reported by the authors may well exacerbate health problems through psychosocial and behavioral means in those studied, as well as others that participated in the cleanup process. How, then, would the authors and physicians in general interpret the relevance of their statistical findings, especially when comparing a predominantly male group of younger cases to a predominantly female group of older controls, and how would they communicate these biomarker results to their patients?
      TableClinical Ranges for Normal Healthy Adult Female and Male Subjects for the Liver Function and Hematological End Points under Study
      Normal Clinical RangesUnexposedExposed
      Clinical biomarkerLow
      From the National Library of Medicine Web site.2
      High
      From the National Library of Medicine Web site.2
      Low
      From the Mayo Clinic Web site.3
      High
      From the Mayo Clinic Web site.3
      Low
      From the Agency for Toxic Substances Disease Registry Web site.4
      High
      From the Agency for Toxic Substances Disease Registry Web site.4
      Low
      Values from Table 2 in D'Andrea and Reddy (2013).1
      High
      Values from Table 2 in D'Andrea and Reddy (2013).1
      Platelets, mcL150,000400,000150,000450,000192,300346,900200,300303,900
      Hemoglobin, gm/dL (females)12.115.11215.51215.2
      Hemoglobin, gm/dL (males)13.817.213.517.513.616.2
      Hematocrit, % (females)36.144.334.944.535.845.8
      Hematocrit, % (males)40.750.338.85041.248
      BUN, mg/dL6207208.322.51016.8
      Creatinine, mg/dL (females)0.61.10.61.2
      Creatinine, mg/dL (males)0.71.30.81.2
      ALP, IU/L441474511534.388.15597.6
      AST, IU/L10348487.737.94.757.3
      ALT, IU/L10407552.856.88.261.4
      Urinary phenol5.913.1
      ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen.
      From the National Library of Medicine Web site.

      National Library of Medicine. MedLine Plus. Available at: http://www.nlm.nih.gov/medlineplus/. Accessed September 18, 2013.

      From the Mayo Clinic Web site.

      Mayo Clinic. Available at: http://www.mayoclinic.com. Accessed September 18, 2013.

      From the Agency for Toxic Substances Disease Registry Web site.

      Agency for Toxic Substances Disease Registry, Centers for Disease Control and Prevention. Available at: http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed September 18, 2013.

      § Values from Table 2 in D'Andrea and Reddy (2013).
      • D'Andrea M.A.
      • Reddy G.K.
      Health consequences among subjects involved in Gulf oil spill clean-up activities.
      Beyond biases in interpreting their biomarker data, no attempt at reconstructing exposure also is a problem. We acknowledge the difficulty and uncertainty in retrospectively reconstructing exposures, but some level of exposure assessment beyond the label of cleanup worker is necessary. The authors do not include critical elements of an exposure assessment such as individual environmental and occupational health histories. Environmental and occupational histories would shed light on relevant concomitant non-oil-spill exposures, pre-, during-, and postspill activities and exposures that need to be considered, and any use of personal protective equipment during cleanup activities that should be accounted for. In short, these authors do not appear to have followed acceptable clinical practice as established by members of the Association of Occupational and Environmental Health Clinics.
      We do commend these authors for their focus on the health of oil spill cleanup workers. Although they do describe, in part, some limitations of their study, the obvious influences these have on the results of their statistical testing and ultimately, on their biased conclusions, are problematic. These problems affect the validity of their conclusions and indirectly threaten to further stress our Gulf Coast communities.

      References

        • D'Andrea M.A.
        • Reddy G.K.
        Health consequences among subjects involved in Gulf oil spill clean-up activities.
        Am J Med. 2013; 126: 966-974
      1. National Library of Medicine. MedLine Plus. Available at: http://www.nlm.nih.gov/medlineplus/. Accessed September 18, 2013.

      2. Mayo Clinic. Available at: http://www.mayoclinic.com. Accessed September 18, 2013.

      3. Agency for Toxic Substances Disease Registry, Centers for Disease Control and Prevention. Available at: http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed September 18, 2013.

      Linked Article

      • Health Consequences among Subjects Involved in Gulf Oil Spill Clean-up Activities
        The American Journal of MedicineVol. 126Issue 11
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          Oil spills are known to affect human health through the exposure of inherent hazardous chemicals such as para-phenols and volatile benzene. This study assessed the adverse health effects of the Gulf oil spill exposure in subjects participating in the clean-up activity along the coast of Louisiana.
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      • The Reply
        The American Journal of MedicineVol. 127Issue 9
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          We appreciate the comments of Wickliffe et al1 on our article published recently in The American Journal of Medicine.2 We strongly disagree with both their opinion and conclusions. We followed very well-established standard study designs for clinical research and the outcomes (clinical biomarkers). The results were subsequently interpreted and discussed appropriately with existing literature. With regard to their criticisms, we have serious concerns about their analysis of the data presented in our published article.
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