This article has Open Peer Review reports available.
The MDRD equation underestimates the prevalence of CKD among blacks and overestimates the prevalence of CKD among whites compared to the CKD-EPI equation: a retrospective cohort study
© Arora et al; licensee BioMed Central Ltd. 2012
Received: 23 May 2011
Accepted: 20 January 2012
Published: 20 January 2012
Black individuals are far more likely than white individuals to develop end stage renal disease (ESRD). However, earlier stages of chronic kidney disease (CKD) have been reported to be less prevalent among blacks. This disparity remains poorly understood. The objective of this study was to evaluate whether the lower prevalence of CKD among blacks in early stages of CKD might be due in part to an inability of the MDRD equation to accurately determine early stages of CKD in both the black and white population.
We conducted a retrospective cohort study of 97, 451 patients seen in primary care clinic in Veterans Integrated Service Network 2 (VISN 2) over a 7 year period to determine the prevalence of CKD using both the Modification of Diet in Renal Disease (MDRD) Study equation and the more recently developed CKD Epidemiology Collaboration (CKD-EPI) equation. Demographic data, comorbid conditions, prescription of medications, and laboratory data were recorded. Logistic regression and quantile regression models were used to compare the prevalence of estimated glomerular filtration rate (eGFR) categories between black and white individuals.
The overall prevalence of CKD was lower when the CKD-EPI equation was used. Prevalence of CKD in whites was 53.2% by MDRD and 48.4% by CKD-EPI, versus 34.1% by MDRD and 34.5% by CKD-EPI in blacks. The cumulative logistic regression and quantile regression showed that when eGFR was calculated by the EPI method, blacks were as likely to present with an eGFR value less than 60 mL/min/1.73 m2 as whites. Using the CKD-EPI equation, blacks were more likely than white individuals to have stage 3b, 4 and 5 CKD. Using the MDRD method, the prevalence in blacks was only higher than in whites for stage 4 and 5 CKD. Similar results were obtained when the analysis was confined to patients over 65 years of age.
The MDRD equation overestimates the prevalence of CKD among whites and underestimates the prevalence of CKD in blacks compared to the CKD-EPI equation.
The incidence and prevalence of both CKD and ESRD in the United States continue to increase . Age-adjusted ESRD rates are much higher for black individuals than white individuals (998 versus 273 per million) . This disparity persists even after controlling for hypertension, diabetes, demographic characteristics, socioeconomic status and access to health care [3, 4]. However studies have shown that the prevalence of early stages of CKD is lower in the black population. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationally representative sample of individuals 45 years and older revealed that estimated GFR < 60 ml/min/1.73 m2 was present in 49.9% of white participants compared to 33.7% of blacks . The National Health and Nutrition Examination Survey (NHANES) III showed similar results . Thus the relationship of the racial prevalence of CKD to ESRD is complex, and not dependent solely on the prevalence of CKD.
These previous studies used a single serum creatinine measurement to determine the estimated GFR, the presence or absence of CKD, and its staging. The Kidney Disease Outcomes Quality Initiative (KDOQI) definition of CKD requires the determination of at least 2 serum creatinine measurements 3 months apart to document the presence of CKD . The above studies also employed the MDRD equation for determining eGFR, which has been shown to underestimate GFR at higher values [7–9]. The CKD-EPI equation was developed as a more accurate determination of the GFR  and has been found to correlate better with long term risk of end-stage renal disease and mortality in a middle aged population . We determined the prevalence of different stages of CKD using both the MDRD and CKD-EPI equations among the black versus white Veteran population in Veterans Integrated Service Network 2 (VISN 2), a large cohort consisting of all Veteran patients in central and western New York, and compared the use of two versus one serum creatinine in these equations. The objective of this study was to determine whether the lower prevalence of CKD among blacks in early stages of CKD might be due in part to an inability of the MDRD equation to accurately determine early stages of CKD in both the black and white population.
Demographics of final sample
p value for difference
Total # of Patients with ≥ 2 Labs
Per Capita Income ($)
20,000 - 25,000
25,000 - 30,000
Definitions and equations
Age was re-calculated at each serum creatinine measurement as the difference in years between the date of serum creatinine measurement and the date of birth. Patients were stratified based on GFR estimated by MDRD and CKD-EPI formulae.
The re-expressed MDRD  formula used was: eGFR = 175 × (Scr)-1.154 × age-0.203 × 0.742 (if female) × 1.212 (if black), where Scr is serum creatinine in mg/dl and age is expressed in years.
The CKD-EPI  formula used was: eGFR = 141 × min(Scr/k, 1)α × max(Scr/k, 1)-1.209 × 0.993Age × 1.018(if female) × 1.159 (if black), where Scr is serum creatinine in mg/dl, k is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1.
Prevalence was calculated as the ratio of patients with CKD to the total number of patients with at least two eGFR measurements in the duration of follow up. Patients with only one measurement were excluded. CKD was classified into stages based on the KDOQI guidelines  and National Institute for Health and Clinical Excellence (NICE) guidelines  as follows: stage 3a: GFR 45-59 ml/min per 1.73 m2, stage 3b: GFR 30-44 ml/min per 1.73 m2, stage 4: GFR 15-29 ml/min per 1.73 m2, and stage 5: GFR < 15 ml/min per 1.73 m2.
The first recorded creatinine value was used as the index creatinine. CKD stages were stratified based on the index creatinine when only one value of creatinine was used. The stratification into the stages based on the 2 values was done only if both the eGFRs were less than 60 ml/min/1.73 m2 (minimum time before 2nd measurement was 3 months). If the subsequent eGFR was more than 60 ml/min per 1.73 m2 the patient was not considered to have CKD.
Descriptive statistics were produced for the overall population and for the black and white groups separately. The descriptive statistics included patient demographics (age, gender, marital status, per capita income group), clinical variables (BMI, HDL-C, LDL-C, triglycerides) and comorbid conditions: MI, CAD, CHF, PVD, COPD, depression, cancer, diabetes, dyslipidemia, and hypertension). Proportions of patients with the above characteristics in different eGFR categories were compared using χ2 test. Logistic regression was used to determine the effects of baseline characteristics on CKD condition as well as on classification in a particular eGFR category with ≥ 90 ml/min per 1.73 m2 as the reference category. The two methods (EPI and MDRD) of calculation of eGFR were compared using the Cronbach's alpha measure.
Racial differences were explored in several other ways. First we ran individual logistic regressions of each eGFR category with the ≥ 60 mL/min/1.73 m2 category as the reference level. We computed both unadjusted and adjusted odds ratios for blacks. Next we ran the cumulative logistic regressions comparing patients at a given level of eGFR with patients above that level. Again we computed both unadjusted and adjusted odds ratios for the African-American group. The adjusted model included age, gender, COPD, cerebrovascular event, depression, cancer, diabetes, dyslipidemia, hypertension, BMI group, presence of any vascular disease and proteinuria. As the distribution of patients, especially blacks, was not normal, and we were interested in the lower end of the distribution of eGFR, quantile regression models were built to examine the change in the race parameter over different percentiles. These models adjusted for the same variables used in the logistic regression models but also included a fourth-order polynomial of age. As there were significant age differences between whites and blacks, sensitivity analyses were done for patients above age 65 years. All the analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). Statistical significance was set α = 0.05.
Patients with CKD (eGFR < 60 ml/min by CKD-EPI) with various comorbidities
Total # of Patients with ≥ 2 Labs
Any Vascular Disease
HDL < 40 mg/dL
LDL > 100 mg/dL
TG > 200 mg/dL
Racial difference (Black vs. White) in eGFR distribution and odds ratio in cumulative logistic model
≤ 89 Vs. ≥ 90
0.629 (0.595 to 0.665)
0.404 (0.382 to 0.427)
≤ 59 Vs. ≥ 60
1.057 (0.981 to 1.139)
0.669 (0.623 to 0.72)
≤ 44 Vs. ≥ 45
1.238 (1.114 to 1.376)
1.061 (0.951 to 1.184)
≤ 29 Vs. ≥ 30
1.616 (1.378 to 1.895)
1.498 (1.267 to 1.771)
< 15 Vs. ≥ 15
3.171 (2.458 to 4.09)
3.062 (2.35 to 3.989)
We studied the prevalence of different stages of CKD among blacks and whites in > 180,000 patients who were seen in primary care clinic at VISN2, using MDRD and CKD-EPI equations. The cumulative logistic regression adjusted for age and other comorbidities showed that when eGFR was calculated by the CKD- EPI method, blacks were as likely as whites to present with an eGFR value less than 60 mL/min/1.73 m2. Using the CKD-EPI equation, blacks were more likely than white individuals to have stage 3b, 4 and 5 CKD. When eGFR was calculated by the MDRD method, the results were similar for values below 30 mL/min/1.73 m2. There was considerable difference between the two methods above this value. Similar results were also shown when quantile regression was used or analysis was confined to patients above age 65 years.
It is well established that the risk for ESRD is higher in black than white individuals, yet earlier stages of CKD have been found to be more prevalent in whites [1–5, 14, 15]. Clase et. al. examined the NHANES III database and found that the prevalence rate of CKD (eGFR < 60 ml/min/1.73 m2 by the original MDRD equation ) in non-diabetic black males, black females, white males, and white females was 4.2%, 6.2%, 9.2%, and 17.8%, respectively . Coresh et.al. evaluated the NHANES III database including diabetic individuals and found a prevalence of eGFR < 60 ml/min per 1.73 m2 in 3.4% of black participants and 5.0% in white participants using a single measurement of serum creatinine in the simplified MDRD study equation . In REGARDS, McClellan et. al. found that the prevalence of an eGFR < 60 ml/min per 1.73 m2 was 33.7% in black patients and 49.9% in white patients using a single serum creatinine . They examined the prevalence at different deciles of eGFR and using eGFR > 60 ml/min per 1.73 m2as the reference, found that the odds ratio for a low eGFR in blacks compared to whites increased as kidney function declined, with an odds ratio of .46 for eGFR 50 to 59 ml/min per 1.73 m2 to an odds ratio of 2.56 for an eGFR of 10-20 ml/min per 1.73 m2. This relationship held true even after adjusting for age, gender, diabetes, hypertension, history of myocardial infarction or stroke, smoking status, and region of the country.
This inconsistency in prevalence between blacks and whites in early CKD versus ESRD remains unexplained. Several factors which have been proposed to explain this [3, 4, 14, 18–29]. There may be more rapid progression of CKD in blacks due to less effective treatment of modifiable risk factors affecting the progression of CKD [18–22] or differences in genetic [23, 24] and environmental  factors. Black patients with CKD may have a lower death rate and be more likely to reach ESRD. Newsome et al found that in a large cohort of CKD patients who had suffered a myocardial infarction, black patients had better survival after 3 years . However, NHANES III data showed that black individuals with CKD under 65 years of age were more likely to die than white individuals, but there was no difference seen in individuals over 65 years of age . Likewise, a study using the VA national database showed a higher mortality for black patients versus white patients at all levels of baseline GFR . We did not examine mortality in this study.
Blacks may have higher prevalence of ESRD relative to CKD because they present to the health care system later in the course of kidney disease , we found no difference in baseline CKD-EPI eGFRs at time of entry to the VA system between black and white individuals (Figure 3). There may be differences in quality of care given to blacks compared to whites. A study showed decreased use of cardiovascular procedures in minorities which may affect morbidity and mortality from cardiovascular events . However, a study of treatment regimens for CKD in the Department of Defense found similar compliance of care for stage 3 and 4 CKD in black and white individuals .
Another explanation for lower prevalence of CKD among the black population could be the lack of accurate tools to estimate GFR. The MDRD equation was derived from a large study of patients with chronic renal disease  which includes a correction factor of 20.5% for blacks for the same creatinine level compared to whites. This equation is widely used in clinical laboratories to estimate GFR. However it has been shown that this equation tends to underestimate GFR in healthy individuals [7, 8]. The CKD-EPI equation was derived more recently in an attempt to rectify the fact that the MDRD equation underestimated measured GFR at higher values . This equation was found to be more accurate than the MDRD equation, especially at higher GFRs. The sample populations used to develop the CKD-EPI equation and the MDRD equation had a limited number of elderly patients. However, the CKD-EPI population included 32% blacks compared to only 15% in the MDRD sample population. So it may be possible that CKD-EPI is a better equation for GFR estimation in blacks. Delanaye et. al. recently found a prevalence of stage 3 CKD of 11.04% using the MDRD equation versus 7.98% using the CKD-EPI equation in a screen of 1992 individuals . Their study used a single creatinine measurement to define CKD and there were no black patients in their study population.
In the present study, when GFR was determined by CKD-EPI compared to MDRD, we found that the prevalence of earlier stages of CKD was not different in blacks compared to whites. Additional file 1 Table 4 shows why there were significant differences in classification of stages of CKD using the 2 formulas. The patients who were initially classified in different eGFR categories by CKD-EPI method were reclassified again by applying MDRD equation. In the overall patient group, 44.4% of patients who were classified into the > 90 ml/min per 1.73 m2 eGFR group by CKD-EPI were re-classified by MDRD to the lower eGFR category of 60-89 ml/min per 1.73 m2. The overall difference in the prevalence of patients falling in to the 60-89 ml/min per 1.73 m2 eGFR group increased by about 3.4% by using CKD-EPI (5.7% - 2.3% = 3.4%). The most noticeable finding was a large increase in the number of black individuals found to have stage 3a CKD (17% higher) when determined by CKD-EPIwho were classified to a no-CKD category (eGFR of 60-89 ml/min per 1.73 m2) by MDRD method. The number of white patients classified as stage 3a did not change. Similarly, 6% of the whites who were initially classified into an eGFR of 60-89 ml/min per 1.73 m2 (No-CKD category) by CKD-EPI method were reclassified to an eGFR category of 45-59 ml/min per 1.73 m2 (CKD stage 3a) by MDRD method. These observations suggest that the lower prevalence of CKD among black individuals is due to underestimation of earlier stages of CKD in blacks and overestimation of earlier stages of CKD among whites by MDRD method.
There are certain limitations to this study. First, we have not directly measured GFR. Proteinuria was not included in the evaluation, but this would be more critical to a study of progression rather than classification of CKD. Although the VHA is the largest integrated health care system in United States and utilizes a uniform data collection system, this is a retrospective study and some patients had to be excluded due to lack of information about gender and race. The study was done on individuals in the VA system, and therefore may not be applicable to the general population.
This the first report of the racial prevalence of CKD in a large VA cohort using 2 serum creatinine measurements and employing the CKD-EPI equation to estimate GFR. Using an adjusted regression model, we found no difference in the prevalence of earlier stages of CKD in black individuals relative to white individuals. We found that the previously described higher prevalence of early stage CKD in whites may be accounted for by differences in classification of stages of CKD by the MDRD equation relative to the more recently derived CKD-EPI equation. The finding that the prevalence of early CKD is similar between the two races does not fully explain why ESRD is more prevalent in blacks. Further studies will be required to understand why this racial disparity persists.
This work was supported by a grant from the National Kidney Foundation of Western New York.
- Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS: Prevalence of chronic kidney disease in the United States. JAMA. 2007, 298 (17): 2038-2047. 10.1001/jama.298.17.2038.View ArticlePubMedGoogle Scholar
- United States Renal Data System: USRDS 2009: Annual Report: Atlas of Chronic Kidney Disease and End Stage Renal Disease in the United States, Bethesda, MD. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases. 2009Google Scholar
- McClellan W, Warnock DG, McClure L, Campbell RC, Newsome BB, Howard V, Cushman M, Howard G: Racial differences in the prevalence of chronic kidney disease among participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Study. J Am Soc Nephrol. 2006, 17 (6): 1710-1715. 10.1681/ASN.2005111200.View ArticlePubMedGoogle Scholar
- Xue JL, Eggers PW, Agodoa LY, Foley RN, Collins AJ: Longitudinal study of racial and ethnic differences in developing end-stage renal disease among aged medicare beneficiaries. J Am Soc Nephrol. 2007, 18 (4): 1299-1306. 10.1681/ASN.2006050524.View ArticlePubMedGoogle Scholar
- Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003, 41 (1): 1-12.View ArticlePubMedGoogle Scholar
- K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002, 39 (2 Suppl 1): S1-266.Google Scholar
- Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG: Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med. 2004, 141 (12): 929-937.View ArticlePubMedGoogle Scholar
- Stevens LA, Coresh J, Feldman HI, Greene T, Lash JP, Nelson RG, Rahman M, Deysher AE, Zhang YL, Schmid CH, et al: Evaluation of the modification of diet in renal disease study equation in a large diverse population. J Am Soc Nephrol. 2007, 18 (10): 2749-2757. 10.1681/ASN.2007020199.View ArticlePubMedGoogle Scholar
- Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006, 145 (4): 247-254.View ArticlePubMedGoogle Scholar
- Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, et al: A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009, 150 (9): 604-612.View ArticlePubMedPubMed CentralGoogle Scholar
- Matsushita K, Selvin E, Bash LD, Astor BC, Coresh J: Risk implications of the new CKD Epidemiology Collaboration (CKD-EPI) equation camopared with the MDRD Study equation for estimated GFR: the Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis. 2010, 55: 648-659. 10.1053/j.ajkd.2009.12.016.View ArticlePubMedPubMed CentralGoogle Scholar
- National Institute for Health and Clinical Excellence Guideline C673. Chronic kidney Disease. 2008Google Scholar
- Gaskin DJ, Hoffman C: Racial and ethnic differences in preventable hospitalizations across 10 states. Med Care Res Rev. 2000, 57 (Suppl 1): 85-107.View ArticlePubMedGoogle Scholar
- Choi AI, Rodriguez RA, Bacchetti P, Bertenthal D, Hernandez GT, O'Hare AM: White/black racial differences in risk of end-stage renal disease and death. Am J Med. 2009, 122 (7): 672-678. 10.1016/j.amjmed.2008.11.021.View ArticlePubMedPubMed CentralGoogle Scholar
- Rostand SG, Kirk KA, Rutsky EA, Pate BA: Racial differences in the incidence of treatment for end-stage renal disease. N Engl J Med. 1982, 306 (21): 1276-1279. 10.1056/NEJM198205273062106.View ArticlePubMedGoogle Scholar
- Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999, 130 (6): 461-470.View ArticlePubMedGoogle Scholar
- Clase CM, Garg AX, Kiberd BA: Prevalence of low glomerular filtration rate in nondiabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol. 2002, 13 (5): 1338-1349. 10.1097/01.ASN.0000013291.78621.26.View ArticlePubMedGoogle Scholar
- Hunsicker LG, Adler S, Caggiula A, England BK, Greene T, Kusek JW, Rogers NL, Teschan PE: Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int. 1997, 51 (6): 1908-1919. 10.1038/ki.1997.260.View ArticlePubMedGoogle Scholar
- Hsu CY, Lin F, Vittinghoff E, Shlipak MG: Racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the United States. J Am Soc Nephrol. 2003, 14 (11): 2902-2907. 10.1097/01.ASN.0000091586.46532.B4.View ArticlePubMedGoogle Scholar
- Brancati FL, Whittle JC, Whelton PK, Seidler AJ, Klag MJ: The excess incidence of diabetic end-stage renal disease among blacks. A population-based study of potential explanatory factors. JAMA. 1992, 268 (21): 3079-3084. 10.1001/jama.1992.03490210061036.View ArticlePubMedGoogle Scholar
- Tarver-Carr ME, Powe NR, Eberhardt MS, LaVeist TA, Kington RS, Coresh J, Brancati FL: Excess risk of chronic kidney disease among African-American versus white subjects in the United States: a population-based study of potential explanatory factors. J Am Soc Nephrol. 2002, 13 (9): 2363-2370. 10.1097/01.ASN.0000026493.18542.6A.View ArticlePubMedGoogle Scholar
- Martins D, Tareen N, Norris KC: The epidemiology of end-stage renal disease among African Americans. Am J Med Sci. 2002, 323 (2): 65-71. 10.1097/00000441-200202000-00002.View ArticlePubMedGoogle Scholar
- Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Kajiyama H, Ahuja TS, et al: MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet. 2008, 40 (10): 1175-1184. 10.1038/ng.226.View ArticlePubMedPubMed CentralGoogle Scholar
- Suthanthiran M, Li B, Song JO, Ding R, Sharma VK, Schwartz JE, August P: Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage. Proc Natl Acad Sci USA. 2000, 97 (7): 3479-3484. 10.1073/pnas.050420897.PubMedPubMed CentralGoogle Scholar
- Norris K, Mehrotra R, Nissenson AR: Racial differences in mortality and ESRD. Am J Kidney Dis. 2008, 52 (2): 205-208. 10.1053/j.ajkd.2008.06.004.View ArticlePubMedPubMed CentralGoogle Scholar
- Newsome BB, McClellan WM, Coffey CS, Allison JJ, Kiefe CI, Warnock DG: Survival advantage of black patients with kidney disease after acute myocardial infarction. Clin J Am Soc Nephrol. 2006, 1 (5): 993-999. 10.2215/CJN.01251005.View ArticlePubMedGoogle Scholar
- Mehrotra R, Kermah D, Fried L, Adler S, Norris K: Racial differences in mortality among those with CKD. J Am Soc Nephrol. 2008, 19 (7): 1403-1410. 10.1681/ASN.2007070747.View ArticlePubMedPubMed CentralGoogle Scholar
- Popescu I, Vaughan-Sarrazin MS, Rosenthal GE: Differences in mortality and use of revascularization in black and white patients with acute MI admitted to hospitals with and without revascularization services. JAMA. 2007, 297 (22): 2489-2495. 10.1001/jama.297.22.2489.View ArticlePubMedGoogle Scholar
- Gao SW, Oliver DK, Das N, Hurst FP, Lentine KL, Agodoa LY, Sawyers ES, Abbott KC: Assessment of racial disparities in chronic kidney disease stage 3 and 4 care in the department of defense health system. Clin J Am Soc Nephrol. 2008, 3 (2): 442-449. 10.2215/CJN.03940907.View ArticlePubMedPubMed CentralGoogle Scholar
- Delanaye P, Cavalier E, Mariat C, Maillard N, Krzesinski JM: MDRD or CKD-EPI study equations for estimating prevalence of stage 3 CKD in epidemiological studies: which difference? Is this difference relevant?. BMC Nephrol. 2010, 11: 8-10.1186/1471-2369-11-8.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/13/4/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.