- Research
- Open Access
Maximum likelihood estimation of reviewers' acumen in central review setting: categorical data
- Wei Zhao^{1}Email author,
- James M Boyett^{2},
- Mehmet Kocak^{2},
- David W Ellison^{3} and
- Yanan Wu^{2, 4}
https://doi.org/10.1186/1742-4682-8-3
© Zhao et al; licensee BioMed Central Ltd. 2011
- Received: 9 November 2010
- Accepted: 25 March 2011
- Published: 25 March 2011
Abstract
Successfully evaluating pathologists' acumen could be very useful in improving the concordance of their calls on histopathologic variables. We are proposing a new method to estimate the reviewers' acumen based on their histopathologic calls. The previously proposed method includes redundant parameters that are not identifiable and results are incorrect. The new method is more parsimonious and through extensive simulation studies, we show that the new method relies less on the initial values and converges to the true parameters. The result of the anesthetist data set by the new method is more convincing.
Keywords
- Gaussian Mixture Model
- Anaplastic Astrocytoma
- Grade Category
- Suspicious Result
- Review Diagnosis
1. Introduction
Histopathologic diagnosis and the subclassification of tumors into grades of malignancy are critical to the care of cancer patients, serving as a basis for both prognosis and therapy. Such diagnostic schemes evolve, and this process often involves reproducibility studies to ensure accuracy and clinical relevance. However, studies of existing or novel histopathologic grading schemes often reveal diagnostic variance among pathologists[1–4].
The process of histopathologic evaluation is necessarily subjective; even "objective" assessments as part of the histologic work-up of a tumor, such as the mitotic index, are semi-quantitative at best. While this subjectivity underlies discrepancies between pathologists when several evaluate a series of tumors together, a pathologist's experience and skill with different tumor types, especially uncommon tumors such as some brain tumors, will influence his or her performance in this setting. This factor, pathologist "acumen," could be especially influential when new grading schemes are proposed for uncommon tumors. A corollary of this influence is that discussion among a group of pathologists with different levels of experience or acumen about how best to use histopathologic variables in a new tumor-grading scheme might be expected to improve the concordance of their calls. Although estimating inter- and intra-reviewer agreement is important[5–8], in this paper, we are more interested in evaluating the performance of individual reviewers[9, 10].
is defined as the reviewer's acumen because we are more interested in , j = 1,...J than those error rates. Dawid and Skene[9] proposed a method based on the EM algorithm to estimate . We find that their method has serious drawbacks and may give suspicious results. In particular, their method is over parameterized and doesn't converge to correct parameters for some initial values. We propose a modification to their method, which is also based on the EM algorithm. In the next section, we first derive the incomplete-data likelihood function and then show the EM algorithm solving procedures. We use multiple simulation studies in Section 3 to demonstrate that the new method converges to the correct parameters and relies less on the initial values. Finally, we revisit the anesthetist data used by Dawid and Skene and present a new example of a pathology review data from the Children's Cancer Group (CCG)-945 study[11].
2. Model Reviewer's Acumen
Dawid and Skene used two latent variables to model true category probabilities, a sample specific probability γ_{ ij } (T_{ ij } in the original paper) and population probability p_{ j } , which is the proportion of the j^{ th } category in the population. Since the estimation of p_{ j } can be expressed as a function of , p_{ j } are redundant and not identifiable. Because of this, the modified model doesn't include p_{ j } in the likelihood function and instead, p_{ j } are expressed as a function of γ_{ ij } .
where and Θ = {γ_{ ij } }. Ω are reviewer specific parameters and Θ are sample specific parameters. In total, there are K × J × (J - 1) + N parameters in the model. It is worth noting that the true category probability, γ_{ ij } , is a latent variable and will be estimated in the E step of the EM algorithm.
3. Simplex Based EM Algorithm
The method proposed by Dawid and Skene has a closed form solution for , which is derived from the complete data likelihood function. But, their method is overly parameterized, and the convergence relies heavily on the goodness of initial values. It is easy to see that the estimator of depends solely on its initial values when the estimators of (equation 2.3 in the original paper) and (equation 2.4) are put into equation 2.5 in their paper.
The incomplete data likelihood function, equation 4, is a mixture of multinomial probabilities, in which the mixture probabilities, , are unknown. Although solving the incomplete-data likelihood function directly is intractable, one can solve it iteratively using the EM algorithm. The EM algorithm has been widely used to solve mixture models[12], especially those Gaussian mixture models in genetic mapping studies[13]. The same procedures apply here as well. In E step, we estimate the latent variable, , by averaging the posterior probability of the true category over all reviewers. In M step, we use simplex method to search for that maximize equation 4.
- 1.
where is from the previous iteration and is considered as a prior probability.
- 2.M step: Plug into equation 4 and use the simplex method to search for the that maximizes the incomplete-data likelihood function,
- 3.
Repeat the E step and M step until convergence.
The simplex algorithm, originally proposed by Nelder and Mead[14], provides an efficient way to estimate parameters, especially when the parameter space is large[13]. It is a direct-search method for nonlinear unconstrained optimization. It attempts to minimize a scalar-valued nonlinear function using only function values, without any derivative information (explicit or implicit). The simplex algorithm uses linear adjustment of the parameters until some convergence criterion is met. The term "simplex" arises because the feasible solutions for the parameters may be represented by a polytope figure called a simplex. The simplex is a line in one dimension, a triangle in two dimensions, and a tetrahedron in three dimensions. Since no division is required in the calculation, the "divided by zero" runtime error is avoided.
4. Simulation Study
MLE for the first simulation, in which all reviewers had good acumen
R1 | R2 | R3 | R4 | R5 | R6 | |
---|---|---|---|---|---|---|
| 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 |
| 0.8 | 0.8 | 0.7 | 0.8 | 0.8 | 0.8 |
| 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | 0.7 |
| 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 |
| 0.78 (0.09) | 0.78 (0.09) | 0.78 (0.1) | 0.78 (0.09) | 0.78 (0.09) | 0.78 (0.1) |
| 0.78 (0.09) | 0.78 (0.09) | 0.69 (0.11) | 0.78 (0.09) | 0.78 (0.09) | 0.78 (0.1) |
| 0.8 (0.08) | 0.79 (0.07) | 0.8 (0.09) | 0.8 (0.08) | 0.8 (0.07) | 0.7 (0.1) |
| 0.8 (0.08) | 0.8 (0.08) | 0.8 (0.09) | 0.8 (0.08) | 0.8 (0.08) | 0.81 (0.09) |
MLE for the second simulation, in which all reviewers had weak acumen
R1 | R2 | R3 | R4 | R5 | R6 | |
---|---|---|---|---|---|---|
| 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
| 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
| 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
| 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
| 0.45 (0.16) | 0.46 (0.15) | 0.48 (0.15) | 0.47 (0.16) | 0.49 (0.15) | 0.49 (0.15) |
| 0.45 (0.16) | 0.46 (0.15) | 0.47 (0.16) | 0.48 (0.16) | 0.48 (0.15) | 0.5 (0.15) |
| 0.51 (0.15) | 0.52 (0.15) | 0.52 (0.15) | 0.53 (0.14) | 0.54 (0.14) | 0.54 (0.14) |
| 0.54 (0.16) | 0.54 (0.16) | 0.54 (0.16) | 0.53 (0.15) | 0.53 (0.15) | 0.53 (0.15) |
MLE for the third simulation, in which reviewers had mixed acumen
R1 | R2 | R3 | R4 | R5 | R6 | |
---|---|---|---|---|---|---|
| 0.5 | 0.9 | 0.9 | 0.7 | 0.9 | 0.9 |
| 0.7 | 0.9 | 0.9 | 0.9 | 0.5 | 0.9 |
| 0.8 | 0.7 | 0.6 | 0.9 | 0.9 | 0.9 |
| 0.8 | 0.9 | 0.6 | 0.9 | 0.7 | 0.9 |
| 0.5 (0.16) | 0.88 (0.11) | 0.88 (0.16) | 0.69 (0.14) | 0.88 (0.18) | 0.87 (0.07) |
| 0.7 (0.16) | 0.87 (0.11) | 0.88 (0.17) | 0.87 (0.11) | 0.5 (0.2) | 0.86 (0.08) |
| 0.8 (0.14) | 0.7 (0.12) | 0.6 (0.17) | 0.89 (0.11) | 0.9 (0.17) | 0.88 (0.06) |
| 0.81 (0.14) | 0.91 (0.1) | 0.6 (0.18) | 0.9 (0.1) | 0.7 (0.19) | 0.9 (0.06) |
MLE for the fourth simulation, in which some reviewers had good acumen and some had weak acumen
R1 | R2 | R3 | R4 | R5 | R6 | |
---|---|---|---|---|---|---|
| 0.5 | 0.5 | 0.5 | 0.9 | 0.9 | 0.9 |
| 0.5 | 0.5 | 0.5 | 0.9 | 0.9 | 0.9 |
| 0.5 | 0.5 | 0.5 | 0.9 | 0.9 | 0.9 |
| 0.5 | 0.5 | 0.5 | 0.9 | 0.9 | 0.9 |
| 0.5 (0.11) | 0.5 (0.12) | 0.5 (0.12) | 0.86 (0.08) | 0.86 (0.08) | 0.86 (0.08) |
| 0.5 (0.12) | 0.5 (0.12) | 0.5 (0.12) | 0.86 (0.08) | 0.86 (0.08) | 0.86 (0.08) |
| 0.5 (0.09) | 0.51 (0.1) | 0.51 (0.09) | 0.89 (0.06) | 0.88 (0.07) | 0.88 (0.06) |
| 0.51 (0.09) | 0.51 (0.09) | 0.51 (0.1) | 0.91 (0.06) | 0.9 (0.06) | 0.9 (0.06) |
The estimated values for in all 4 simulation studies converge to true parameter values. The probabilities for categories 3 and 4 are closer to the true values, and the RMSEs are smaller. This is what is expected because categories 3 and 4 have 10 more samples than categories 1 and 2. In general, the RMSE is higher for small probabilities and smaller for large probabilities. In addition, the values for , l ≠ j converge to the true values as well(data not shown).
In Dawid and Skene method, is a saddle point, at which the method converges to itself if used as initial values. However, these initial set of values work well in our method. We define that the computation reaches convergence when the log likelihood function between two iterations is less than 10^{-3}. Although more stringent threshold can be used, we find that 10^{-3} is generally sufficient to guarantee convergence.
5. Examples
5.1 Revisit the Anesthetist data
This data set was used by Dawid and Skene for a demonstration of their method. Briefly, the data came from five anesthetists who classified each patient on a scale of 1 to 4. Anesthetist 1 assessed the patients three times, but we assume that the assessments were independent, as did by the previous authors. Table 4 in their paper gives the estimated probabilities γ_{ ij } for each patient. Most estimates in the table are either 1 or 0, which is very unlikely given the level of disagreement between reviewers in the study.
In the data, observer 1 assigned patient #36 to category 3 twice and category 4 once, observers 2 and 4 assigned the same patient to category 4, and both observers 3 and 5 assigned him to category 3. It was estimated that the patient had 100% probability of being in category 4, . After closely examining the data, we found that category 4 was actually the category to which all observers assigned patients least frequently, and patient #11 was the only one all observers agreed on as being in category 4 and there was no extra data to establish acumen in this category for any reviewers. Because of this observation, their estimate of patient category probability is unrealistic and suspicious. For patient #3, reviewer 1 gave category 1 twice and category 2 once; reviewers 2, 4, 5 gave category 2 and reviewer 3 gave category 1. The patient was estimated 100% in category 2. Results for patients 2, 10, and 14 are also suspicious.
MLE of the observers' acumen (individual error rate) from the anesthetic data
Observer 1 | |||||
---|---|---|---|---|---|
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.87 | 0.13 | 0 | 0 |
2 | 0.03 | 0.88 | 0.09 | 0 | |
3 | 0 | 0.03 | 0.9 | 0.07 | |
4 | 0.01 | 0.05 | 0.07 | 0.87 | |
Observer 2 | |||||
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.79 | 0.21 | 0 | 0 |
2 | 0.05 | 0.65 | 0.3 | 0 | |
3 | 0 | 0 | 0.61 | 0.39 | |
4 | 0.01 | 0.07 | 0.04 | 0.89 | |
Observer 3 | |||||
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.92 | 0.07 | 0.01 | 0 |
2 | 0.04 | 0.83 | 0.13 | 0 | |
3 | 0 | 0.22 | 0.39 | 0.39 | |
4 | 0.1 | 0.08 | 0 | 0.81 | |
Observer 4 | |||||
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.88 | 0.12 | 0 | 0 |
2 | 0.05 | 0.76 | 0.14 | 0.06 | |
3 | 0 | 0 | 0.8 | 0.2 | |
4 | 0.03 | 0.26 | 0.1 | 0.62 | |
Observer 5 | |||||
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.92 | 0.07 | 0.02 | 0 |
2 | 0.19 | 0.63 | 0.18 | 0 | |
3 | 0 | 0.27 | 0.55 | 0.18 | |
4 | 0 | 0 | 0.01 | 0.98 |
Estimated category probability for each patient for the anesthetist data
Category | Category | ||||||||
---|---|---|---|---|---|---|---|---|---|
Patient | 1 | 2 | 3 | 4 | Patient | 1 | 2 | 3 | 4 |
1 | 1 | 0 | 0 | 0 | 24 | 0.14 | 0.86 | 0 | 0 |
2 | 0 | 0 | 0.95 | 0.05 | 25 | 1 | 0 | 0 | 0 |
3 | 0.5 | 0.5 | 0 | 0 | 26 | 1 | 0 | 0 | 0 |
4 | 0.24 | 0.76 | 0 | 0 | 27 | 0 | 0.93 | 0.07 | 0 |
5 | 0 | 1 | 0 | 0 | 28 | 1 | 0 | 0 | 0 |
6 | 0 | 1 | 0 | 0 | 29 | 1 | 0 | 0 | 0 |
7 | 0.68 | 0.32 | 0 | 0 | 30 | 0.82 | 0.18 | 0 | 0 |
8 | 0 | 0 | 1 | 0 | 31 | 1 | 0 | 0 | 0 |
9 | 0 | 1 | 0 | 0 | 32 | 0 | 0 | 1 | 0 |
10 | 0 | 0.85 | 0.15 | 0 | 33 | 1 | 0 | 0 | 0 |
11 | 0 | 0 | 0 | 1 | 34 | 0 | 1 | 0 | 0 |
12 | 0 | 0.65 | 0.35 | 0 | 35 | 0 | 0.93 | 0.07 | 0 |
13 | 1 | 0 | 0 | 0 | 36 | 0 | 0 | 0.73 | 0.27 |
14 | 0.11 | 0.89 | 0 | 0 | 37 | 0.14 | 0.85 | 0.02 | 0 |
15 | 0.99 | 0.01 | 0 | 0 | 38 | 0 | 0.51 | 0.49 | 0 |
16 | 1 | 0 | 0 | 0 | 39 | 0 | 0 | 1 | 0 |
17 | 1 | 0 | 0 | 0 | 40 | 1 | 0 | 0 | 0 |
18 | 1 | 0 | 0 | 0 | 41 | 1 | 0 | 0 | 0 |
19 | 0 | 1 | 0 | 0 | 42 | 0.89 | 0.11 | 0 | 0 |
20 | 0.1 | 0.9 | 0 | 0 | 43 | 0 | 0.93 | 0.07 | 0 |
21 | 0 | 1 | 0 | 0 | 44 | 0.99 | 0.01 | 0 | 0 |
22 | 0 | 1 | 0 | 0 | 45 | 0 | 1 | 0 | 0 |
23 | 0 | 1 | 0 | 0 |
5.2 Empirical Study: CCG-945
MLE of the reviewers' acumen for the CCG-945 data
Reviewer 1 | |||||
---|---|---|---|---|---|
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.78 | 0.12 | 0.09 | 0.00 |
2 | 0.15 | 0.85 | 0.00 | 0.00 | |
3 | 0.49 | 0.15 | 0.30 | 0.07 | |
4 | 0.13 | 0.02 | 0.09 | 0.76 | |
Reviewer 2 | |||||
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 1.00 | 0.00 | 0.00 | 0.00 |
2 | 0.42 | 0.52 | 0.03 | 0.03 | |
3 | 0.32 | 0.15 | 0.32 | 0.20 | |
4 | 0.00 | 0.00 | 0.07 | 0.93 | |
Reviewer 3 | |||||
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.79 | 0.15 | 0.00 | 0.06 |
2 | 0.08 | 0.88 | 0.00 | 0.04 | |
3 | 0.22 | 0.15 | 0.38 | 0.26 | |
4 | 0.32 | 0.04 | 0.05 | 0.60 | |
Reviewer 4 | |||||
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.62 | 0.21 | 0.01 | 0.15 |
2 | 0.14 | 0.76 | 0.06 | 0.03 | |
3 | 0.00 | 0.29 | 0.58 | 0.13 | |
4 | 0.02 | 0.00 | 0.06 | 0.93 | |
Reviewer 5 | |||||
Observed Response | 1 | 2 | 3 | 4 | |
True Response | 1 | 0.82 | 0.06 | 0.06 | 0.07 |
2 | 0.30 | 0.68 | 0.00 | 0.02 | |
3 | 0.51 | 0.13 | 0.36 | 0.00 | |
4 | 0.25 | 0.04 | 0.13 | 0.58 |
It is interesting to see that reviewers have different level of acumen to differentiate AA from GBM based on the revised WHO criteria. If we assume 80% sensitivity (or specificity) is an indicator of good acumen, reviewers 1 and 3 are very experienced in grading AA and GBM, and reviewer 2 clearly needs some improvement. None of the reviewers did well in grading category 3, i.e. other high-grade gliomas. This is somewhat expected because it is the least frequent and most heterogeneous category. When the true category is 4, reviewers 1, 3, and 5 all assigned a noticeable proportion to category 1. The reason may be that some low-grade gliomas in category 4 are difficult to differentiate from AA according to WHO criteria.
6. Conclusion
However, when their method converges, it may converge to suspicious results, as was shown in their example.
Our method is less dependent on initial values and converges to similar values from any reasonable initial values. Because our method starts with the incomplete data likelihood, there is no closed form solution for , and solving equation 4 directly is intractable. We adopted the EM algorithm, which is widely used in solving Gaussian mixture models, for this formidable task. In the M step, we used the simplex method to search for parameters that maximize the incomplete data likelihood function.
In cases when a reviewer is uncertain about a particular sample, the same sample can be recorded multiple times to different categories. No modification to the model is necessary. Using simulation studies, we have shown that our method performs well at a variety of scenarios with fairly small sample sizes. Our model has K × J × (J - 1) + N parameters, J-1 fewer than Dawid and Skene's model. Because the model is highly parameterized, it would be naive to expect any of the theoretical large sample optimality properties to hold[9]. This work focuses entirely on estimating reviewers' acumen, and no hypothesis testing is discussed. We believe that the issue of hypothesis testing can be addressed using a likelihood ratio test[16] and bootstrap method[17]. The reliability of the parameter estimation can be assessed using bootstrap method techniques as well, but it is not the focus of this work. The R program used for the simulation studies and for analyzing the anesthetic data is available upon request.
Declarations
Acknowledgements
We thank Mi Zhou in the St. Jude Hartwell Center for providing computational assistance; we also want to thank David Galloway in St. Jude Scientific Editing for professional support. This work was supported in part by the American Lebanese Syrian Associated Charities.
Authors’ Affiliations
References
- Stenkvist B, Bengtsson E, Eriksson O, Jarkrans T, Nordin B, Westman-Naeser S: Histopathological systems of breast cancer classification: reproducibility and clinical significance. J Clin Pathol. 1983, 36: 392-398. 10.1136/jcp.36.4.392.PubMed CentralView ArticlePubMedGoogle Scholar
- Tihan T, Zhou T, Holmes E, Burger PC, Ozuysal S, Rushing EJ: The prognostic value of histological grading of posterior fossa ependymomas in children: a Children's Oncology Group study and a review of prognostic factors. Mod Pathol. 2008, 21: 165-177.PubMedGoogle Scholar
- Longacre Teri, Ennis Marguerite, Quenneville Louise, Bane Anita, Bleiweiss Ira, Carter Beverley, Catelano Edison, Hendrickson Michael, Hibshoosh Hanina, Layfield Lester, Memeo Lorenzo, Wu Hong, O'Malley Frances: Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study. Mod Pathol. 2006, 19: 195-207. 10.1038/modpathol.3800496.View ArticlePubMedGoogle Scholar
- Izadi-Mood Narges, Yarmohammadi Maryam, Ahmadi Ali Seyed, Irvanloo Guity, Haeri Hayedeh, Meysamie Pasha Ali, Khaniki Mahmood: Reproducibility determination of WHO classification of endometrial hyperplasia/well differentiated adenocarcinoma and comparison with computerized morphometric data in curettage specimens in Iran. Diagnostic Pathology. 2009, 4: 10-10.1186/1746-1596-4-10.PubMed CentralView ArticlePubMedGoogle Scholar
- Cohen Jacob: A coefficient of agreement for nominal scales. Educational and Psychological Measurement. 1960, 20 (1): 37-46. 10.1177/001316446002000104.View ArticleGoogle Scholar
- Fleiss JL: Statistical methods for rates and proportions. 1981, New York: John WileyGoogle Scholar
- Landis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics. 1977, 33: 159-174. 10.2307/2529310.View ArticlePubMedGoogle Scholar
- Barnhart HX, Williamson JM: Modeling concordance correlation via GEE to evaluate reproducibility. Biometrics. 2001, 57: 931-940. 10.1111/j.0006-341X.2001.00931.x.View ArticlePubMedGoogle Scholar
- Dawid P, Skene AM: Maximum likelihood estimation of observer rates using the EM algorithm. Journal of the Royal Statistical Society. Series C (Applied Statistics). 1979, 28 (1): 20-28.Google Scholar
- Hui Siu, Zhou Xiao: Evaluation of diagnostic tests without gold standards. Statistical Methods in Medical Research. 1998, 7: 354-370. 10.1191/096228098671192352.View ArticlePubMedGoogle Scholar
- Pollack Ian, Boyett James, Yates Allan, Burger Peter, Gilles Floyd, Davis Richard, Finlay Jonathan, for the Children's Cancer Group: The influence of central review on outcome associations in childhood malignant gliomas: Results from the CCG-945 experience. Neuro-Oncology. 2003, 5: 197-207. 10.1215/S1152851703000097.PubMed CentralView ArticlePubMedGoogle Scholar
- Hastie Trevor, Tibshirani Robert, Friedman Jerome: The EM algorithm. The Elements of Statistical Learning. 2001, New York: SpringerView ArticleGoogle Scholar
- Zhao W, Wu RL, Ma C-X, Casella G: A fast algorithm for functional mapping of complex traits. Genetics. 2004, 167: 2133-2137. 10.1534/genetics.103.024844.PubMed CentralView ArticlePubMedGoogle Scholar
- Nelder JA, Mead R: A simplex method for function minimization. Comput J. 1965, 7: 308-313.View ArticleGoogle Scholar
- Kleihues P, Burger PC, Scheithauer BW: Histological typingof tumours of the central nervous system. International Histological Classification of Tumours. 1993, 21: 11-16.Google Scholar
- Casella G, Berger RL: Statistical Inference. 2001, Belmont: Duxbury PressGoogle Scholar
- Efron B, Tibshirani RJ: An introduction to the bootstrap. 1993, Boca Raton:Chapman & Hall/CRCView ArticleGoogle Scholar
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