Abstract
Purpose:
Racial disparities for overall survival (OS) in head and neck cancer have been well described. However, the extent to which these disparities exist for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), and the contribution of demographic, clinical, and socioeconomic status (SES) variables, is unknown.
Materials and Methods:
Patients were identified from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE), a population-based study in North Carolina. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for OS in black versus white patients with sequential adjustment sets.
Results:
A total of 157 HPV-associated OPSCC patients were identified. Of these, 93% were white and 7% were black. Black patients with HPV-associated OPSCC were more likely to be younger, have an income <$20,000, live farther away from clinic where biopsy was performed, and have advanced T stage at diagnosis. Black patients had worse OS in the unadjusted analysis (HR 4.9, 95% CI 2.2–11.1, p<0.0001). The racial disparity in OS slightly decreased when sequentially adjusting for demographic, clinical, and SES variables. However, HR for black race remained statistically elevated in the final adjustment set which controlled for age, sex, stage, smoking, alcohol use, and individual-level household income, insurance, and education level (HR 3.4, 95% CI 1.1–10.1, p=0.028).
Conclusion:
This is the first population-based study that confirms persistence of racial disparities in HPV-associated OPSCC after controlling for demographic, clinical, and individual-level socioeconomic factors.
Keywords: Head and neck neoplasms, disparities, race, survival, human papillomavirus
1.1. Introduction
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the United States, affecting approximately 65,410 new patients in 2019.1,2 Over the past three decades, HNSCC epidemiology has changed significantly due to the rapidly increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC).3 This is primarily driven by rising exposure to the human papillomavirus (HPV) infection, which now accounts for 60–70% of incident OPSCC cases.4 Compared to HPV-negative OPSCC, the demographic profile of patients with HPV-positive OPSCC tends to be younger, male, white, and non-smokers.4 It is estimated that there are 3,500 new cases of HPV-associated OPSCC diagnosed in women and 15,500 in men each year in the United States.5 White patients with OPSCC in the United States are more likely than black patients to have HPV-positive tumors (67.6% vs. 42.3%, respectively; p<0.001).6 Most studies evaluating the prognosis for patients with OPSCC have been composed of primarily of white patients. To date, there is limited information regarding the prognosis of black patients with HPV-associated OPSCC.
Racial disparities in HNSCC have been well described, but it is unknown if these findings translate to HPV-associated OPSCC, which is now recognized as a distinct clinicopathologic entity. Although black patients account for a minority of all HNSCC cases, they contribute disproportionately to the morbidity and mortality associated with this disease.7,8 Black HNSCC patients are diagnosed at more advanced disease stage and have worse survival outcomes compared to white HNSCC patients.9–11 Previous studies have suggested that lower socioeconomic status and differential access to care contribute to this disparity.11–14 Some studies have shown that the racial disparities in HNSCC are largely driven by the OPSCC subsite, given that HPV-associated disease is more prevalent in white patients and has better prognosis.15–18 However few studies have examined racial disparities in OPSCC while also assessing the relative influence of HPV-status.
We recently conducted a systematic review of studies assessing racial disparities in OS in OPSCC after adjusting for HPV-status.18 There were only 5 studies in the current literature that examined survival disparities by race after adjusting for HPV-status in OPSCC,19–23 and none included measures of SES in the adjustment set. Furthermore, only one study included alcohol use in the adjustment set. Our findings suggested that HPV-status accounts for much of the racial disparity in OS for OPSCC, but our conclusions were limited by the small number of relevant studies and narrow adjustment sets.
To address this gap in current literature we examined racial differences in HPV-associated OPSCC outcomes using a population-based study with information on individual level-SES, as well as comprehensive demographic, clinical, and treatment variables. Previous studies examining racial disparities have relied either on single-institution data, clinical trial data, or cancer registry data in which this information was not available.
1.2. Methods
1.2.1. Study Population
Data for this analysis was obtained from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE), a population-based study in North Carolina.24 Eligible cases were diagnosed with their first primary squamous cell carcinoma of the oral cavity, pharynx, and larynx diagnosed between January 1st, 2002 and February 28th, 2006; were ages 20 to 80 years at diagnosis; and resided in a 46-county region in central North Carolina. Case ascertainment relied on rapid identification of newly diagnosed cancer cases through the North Carolina Central Cancer Registry (NCCCR). The cancer registrars of 54 hospitals in the study area were contacted monthly to identify potentially eligible cases. Potentially eligible study subjects were mailed a brochure describing the purpose of the study, and upon consent, a study nurse conducted an at-home in-person interview. There were 1381 cases of HNSCC in CHANCE. Our present analysis included only tumors that were p16+ and classified as oropharynx cancers (C01.9, C02.4, C05.1, C05.2, C09.0, C09.1, C09.8, C09.9, C10.0–C10.4, C10.8, and C10.9). Samples that failed p16 typing were not included. Staging classification was based on the American Joint Commission on Cancer (AJCC) 8th edition. This study was approved by the Institutional Review Board at the University of North Carolina at Chapel Hill.
1.2.2. Questionnaire and Covariate measurement
Demographic, lifestyle, oral health, diet, and other common risk factor information were collected using a structured questionnaire during an in-home visit conducted by trained nurse-interviewers. Potential confounders were selected a priori based on their potential associated with survival. These included age, race, gender, education, annual income, smoking, and alcohol consumption. Covariates obtained from the questionnaire included age, sex, race; pack-years of cigarette smoking; ever-consumption of alcohol products; whether the subject was covered by health insurance on diagnosis date, what type of insurance the subject was covered by; household income, and highest attained education level. Race was self-reported from a list of the following options: white, black, American Indian, Alaskan Native, Asian/Pacific Islander, other, and don’t know. Given the low number of other and unknown race (n=28), we focused our analysis on patients who self-identified as white or black. Clinical information such as TNM stage and primary treatment were abstracted from the subjects’ medical record and reviewed by a pathologist and head neck cancer surgeon. Tumor HPV-status was assessed using p16 immunohistochemistry, and the full protocol has been previously reported in detail.25
1.2.3. Survival Assessment
CHANCE data were linked to the National Death Index (NDI) based on name, social security number, date of birth, sex, race, and state of residence to identify deaths through December 31, 2013. The NDI is a national file of identified death record information, including cause of death compiled from computer files submitted by State Vital Statistics offices. Greater than 75% of the CHANCE cases were perfect or near-perfect NDI matches on social security number, date of birth, and sex. The remaining near-matches were confirmed by examining the United States Social Security Death Index and obituaries on newspaper websites. We chose 5-year overall survival as our endpoint for this study, as there is a decreased contribution by the tumor to overall survival after this timepoint. Disease-specific survival was not available for this analysis secondary to lack of data on specific cause of death for patients in CHANCE.
1.2.4. Statistical Analysis
Descriptive statistics were calculated, and bivariate testing methods included t and chi-squared tests. Overall survival (OS) was calculated as time from diagnosis to either date of death due to any cause or censoring on December 31st, 2013 for individuals who were still alive, whichever came first. Subjects who were still alive on December 31st, 2013 were censored on that date. Hazard ratios (HRs) and 95% confidence intervals (CI) for the independent effects of race on overall survival were estimated by Cox proportional hazards regression models. Sequential adjustment sets were used to examine the relative contribution of demographic, clinical and SES variables to the racial survival disparity. Variables that were missing >10% of observations were left out of the survival analysis, which was determined as an a priori threshold. These included rural/urban household designation (n=44 missing) and driving distance to clinic where biopsy was performed (n=49 missing). All variables were treated as categorical variables for the survival models. The proportional hazards assumption was met for all covariates and there was no evidence of multicollinearity on variance inflation factor testing. STATA 16 (StataCorp, College Station, TX) was used for all analyses.
1.3. Results
1.3.1. Baseline Characteristics
There were 157 patients diagnosed with HPV-positive OPSCC. Of these, 146 patients identified as white and 11 as black. Baseline characteristics are summarized (Table I). The majority of patients were male (82%) and between 50 to 65 years of age (53%). Forty-two percent of individuals in our sample had an education of high school or less. Eleven percent had no medical insurance, and 18% had a household income of less than $20,000. The majority of patients in our sample reported at least a 10 pack-year smoking history (57%) and reported drinking alcohol (83%). The most common treatment modality was chemoradiation (39%), followed by surgery with adjuvant chemoradiation (26%). Twenty-nine percent of patients had advanced T stage at diagnosis. Interestingly, only 2 out of the 157 patients presented with distant metastases.
Table I:
Baseline characteristics in HPV-associated OPSCC stratified by race
| Race | White | Black | |||
|---|---|---|---|---|---|
| No. | % | No. | % | P-value | |
| Age | P=0.008 | ||||
| Age < 50 (n=52) | 49 | 34% | 3 | 27% | |
| Age 50 – 65 (n=84) | 76 | 52% | 8 | 73% | |
| Age 65+ (n=21) | 21 | 14% | 0 | 0% | |
| 146 | 100% | 11 | 100% | ||
| Sex | P = 0.997 | ||||
| Male (n=129) | 120 | 82% | 9 | 82% | |
| Female (n=28) | 26 | 18% | 2 | 18% | |
| 146 | 100% | 11 | 100% | ||
| Education | P = 0.086 | ||||
| Less than high school (n=25) | 22 | 15% | 3 | 27% | |
| High school graduate (n=41) | 35 | 24% | 6 | 55% | |
| Education past high school (n=91) | 89 | 61% | 2 | 18% | |
| 146 | 100% | 11 | 100% | ||
| Insurance (relative to private) | P = 0.118 | ||||
| Private insurance (n=93) | 90 | 62% | 3 | 27% | |
| Medicaid/Medicare (n=24) | 21 | 14% | 3 | 27% | |
| No insurance (n=18) | 15 | 10% | 3 | 27% | |
| Other insurance (n=22) | 20 | 14% | 2 | 18% | |
| 146 | 100% | 11 | 100% | ||
| Income | P=0.001 | ||||
| Income > $50,000 (n=75) | 75 | 53% | 0 | 0% | |
| Income $20,000 – $50,000 (n=49) | 45 | 32% | 4 | 36% | |
| Income < $20,000 (n=29) | 22 | 15% | 7 | 64% | |
| 142 | 100% | 11 | 100% | ||
| Rural/Urban Household | P=0.536 | ||||
| Metropolitan (n=90) | 85 | 81% | 5 | 62% | |
| Micropolitan (n=11) | 10 | 10% | 1 | 12% | |
| Rural (n=12) | 10 | 10% | 2 | 25% | |
| 105 | 100% | 8 | 100% | ||
| Driving Time to clinic where biopsy was performed (1st quartile as baseline) | P=0.049 | ||||
| 1st quartile (n=20) | 20 | 20% | 0 | 0% | |
| 2nd quartile (n=31) | 30 | 30% | 1 | 14% | |
| 3rd quartile (n=27) | 26 | 26% | 1 | 14% | |
| 4th quartile (n=30) | 25 | 25% | 5 | 71% | |
| 101 | 100% | 7 | 100% | ||
| Smoking (>10 pack-years) | P=0.228 | ||||
| < 10 Pack Years (n=66) | 64 | 44% | 2 | 18% | |
| > 10 Pack Years (n=90) | 81 | 56% | 9 | 82% | |
| 145 | 100% | 11 | 100% | ||
| Alcohol use | P=0.087 | ||||
| None (n=25) | 24 | 17% | 1 | 10% | |
| Any (n=130) | 121 | 83% | 9 | 90% | |
| 145 | 100% | 10 | 100% | ||
| T Stage | P=0.173 | ||||
| T1 (n=43) | 41 | 28% | 2 | 18% | |
| T2 (n=68) | 66 | 45% | 2 | 18% | |
| T3 (n=24) | 20 | 14% | 4 | 36% | |
| T4 (n=22) | 19 | 13% | 3 | 27% | |
| 146 | 100% | 11 | 100% | ||
| Early (1–2) vs. Advanced T Stage (3–4) | P=0.027 | ||||
| Early T Stage (n=111) | 107 | 73% | 4 | 36% | |
| Advanced T Stage (n=46) | 39 | 27% | 7 | 64% | |
| 146 | 100% | 11 | 100% | ||
| N stage | P=0.857 | ||||
| N0 (n=29) | 26 | 18% | 3 | 27% | |
| N1 (n=93) | 88 | 60% | 5 | 45% | |
| N2 (n=20) | 18 | 12% | 2 | 18% | |
| N3 (n=15) | 14 | 10% | 1 | 9% | |
| 146 | 100% | 11 | 100% | ||
| M Stage | P=0.889 | ||||
| M0 (n=155) | 144 | 99% | 11 | 100% | |
| M1 (n=2) | 2 | 1% | 0 | 0% | |
| 146 | 100% | 11 | 100% | ||
| Treatment Category | P=0.805 | ||||
| Chemotherapy Only (n=1) | 1 | 1% | 0 | 0% | |
| Radiation Only (n=11) | 10 | 7% | 1 | 9% | |
| Surgery Only (n=7) | 7 | 5% | 0 | 0% | |
| Radiation + Chemotherapy (n=61) |
54 | 37% | 7 | 64% | |
| Surgery + Radiation (n=36) | 34 | 23% | 2 | 18% | |
| Surgery + | 40 | 27% | 1 | 9% | |
| Chemoradiation (n=41) | 146 | 100% | 11 | 100% | |
| Number of Treatment Modalities | 0.472 | ||||
| 1 (n=19) | 18 | 12% | 1 | 9% | |
| 2 (n=97) | 88 | 60% | 9 | 82% | |
| 3 (n=41) | 40 | 27% | 1 | 9% | |
| 146 | 100% | 11 | 100% | ||
Compared to white patients, black patients with OPSCC were significantly more likely to be younger, have an income <$20,000, live farther away from clinic where biopsy was performed, and have advanced T stage at diagnosis. Black patients were more likely to have at least a 10 pack-year smoking history (82%) compared to white patients (56%), although this difference was not statistically significant (p=0.228). There were no significant differences by race in terms of treatment type (P=0.805) or number of treatment modalities received (P=0.472). No other baseline characteristics varied significantly by race.
1.3.2. 5-year Overall Survival Analysis
In the unadjusted survival analysis, black HPV-positive OPSCC patients had significantly worse 5-year OS compared to white patients (HR 4.9, 95% CI 2.2–11.1, p<0.0001). We next sequentially adjusted for demographic, clinical, and SES variables. First, after adjustment for age, sex, T stage, N disease, and distant metastases, the racial disparity in 5-year OS remained statistically significant (HR 4.6, 95% CI 1.8–12.0, p=0.002) (Table II). As expected, T4 disease was associated with significantly worse 5-year overall survival compared to T1 disease (HR 2.5, 95% CI 1.0–6.3). Nodal disease and the presence of distant metastases at diagnosis were associated with elevated but non-statistically significant risk of death.
Table II:
5-year Overall Survival in HPV-associated OPSCC adjusted for demographics and stage
| Adjustment with Demographics and Stage* | |||
|---|---|---|---|
| Hazard Ratio | 95% CI | P-Value | |
| Black (vs. white) | 4.6 | 1.8 – 12.0 | 0.002 |
| Age Category (Relative to < 50) | |||
| 50–65 | 0.8 | 0.4 – 1.7 | 0.607 |
| 65+ | 1.3 | 0.5 – 3.5 | 0.577 |
| Female sex (relative to male) | 0.8 | 0.3 – 2.0 | 0.653 |
| T Stage (relative to T1) | |||
| T2 | 0.7 | 0.3 – 1.8 | 0.464 |
| T3 | 1.6 | 0.6 – 4.2 | 0.321 |
| T4 | 2.5 | 1.0 – 6.3 | 0.047 |
| Nodal disease (relative to N0) | 1.7 | 0.7 – 4.2 | 0.253 |
| Distant Metastases (relative to M0) | 5.2 | 0.7 – 41.7 | 0.117 |
Model adjusted for race, age, sex, T stage, nodal disease, and distant metastases
Second, smoking and alcohol use were added to the previous adjustment set. The association between black race and worse 5-year overall survival persisted (HR 4.1, 95% CI 1.5–11.4, p=0.007) (Table III). Neither smoking (>10 pack-years) nor alcohol use was significantly associated with worse overall survival (HR 1.0, 95% CI 0.5–2.2 and HR 1.6, 95% CI 0.5–4.6, respectively).
Table III:
5-year Overall Survival in HPV-associated OPSCC adjusted for demographics, stage, tobacco, and alcohol
| Addition of tobacco and alcohol use* | |||
|---|---|---|---|
| Hazard Ratio | 95% CI | P-Value | |
| Black (vs. white) | 4.1 | 1.5 – 11.4 | 0.007 |
| Age Category (Relative to < 50) | |||
| 50–65 | 0.9 | 0.4 – 2.0 | 0.773 |
| 65+ | 1.4 | 0.5 – 3.9 | 0.531 |
| Female sex (relative to male) | 0.8 | 0.3 – 2.0 | 0.694 |
| T Stage (relative to T1) | |||
| T2 | 0.8 | 0.3 – 1.9 | 0.546 |
| T3 | 1.5 | 0.6 – 4.0 | 0.400 |
| T4 | 2.5 | 1.0 – 6.3 | 0.053 |
| Nodal disease (relative to N0) | 1.7 | 0.7 – 4.2 | 0.267 |
| Distant Metastases (relative to M0) | 4.6 | 0.6 – 36.5 | 0.154 |
| Smoking (> 10 pack-years) | 1.0 | 0.5 – 2.2 | 0.903 |
| Alcohol use (any vs. none) | 1.6 | 0.5 – 4.6 | 0.403 |
Model adjusted for race, age, sex, T stage, nodal disease, distant metastases, smoking, and alcohol use
Finally, individual-level education, household income, and insurance status were added to the previous adjustment set, and the racial disparity remained statistically significant (HR 3.4, 95% CI 1.1–10.1, p=0.028) (Table IV). Having no insurance (HR 3.0, 95% 0.9–9.8) and a household income <$20,000 (HR 1.9, 95% CI 0.5–6.6) were associated with non-significant trends towards worse overall survival in the fully adjusted model.
Table IV:
5-year Overall Survival in HPV-associated OPSCC adjusted for demographics, stage, tobacco, alcohol and SES
| Addition of SES Variables* | |||
|---|---|---|---|
| Hazard Ratio | 95% CI | P-Value | |
| Black (vs. white) | 3.4 | 1.1 – 10.1 | 0.028 |
| Age Category (Relative to < 50) | |||
| 50–65 | 0.8 | 0.4 – 1.9 | 0.698 |
| 65+ | 1.2 | 0.4 – 3.8 | 0.817 |
| Female sex (relative to male) | 0.5 | 0.2 – 1.5 | 0.223 |
| T Stage (relative to T1) | |||
| T2 | 1.0 | 0.4 – 2.6 | 0.985 |
| T3 | 2.2 | 0.8 – 6.3 | 0.131 |
| T4 | 2.4 | 0.9 – 6.3 | 0.081 |
| Nodal disease (relative to N0) | 1.2 | 0.5 – 3.1 | 0.705 |
| Distant Metastases (relative to M0) | 11.4 | 1.2 – 103.4 | 0.031 |
| Smoking (> 10 pack-years) | 0.6 | 0.3 – 1.4 | 0.221 |
| Alcohol use (any vs. none) | 1.3 | 0.4 – 4.0 | 0.672 |
| Education (relative to less than high school) | |||
| High school graduate | 1.0 | 0.3 – 3.0 | 0.973 |
| Additional education past high school | 0.8 | 0.3 – 2.1 | 0.600 |
| Insurance (relative to private insurance) | |||
| Medicaid/Medicare | 4.3 | 1.2 – 15.9 | 0.028 |
| None | 3.0 | 0.9 – 9.8 | 0.071 |
| Other | 2.5 | 0.8 – 7.6 | 0.118 |
| Income (relative to > 50 K) | |||
| Income $20,000 – $50,000 | 0.8 | 0.3 – 2.2 | 0.683 |
| Income < $20,000 | 1.9 | 0.5 – 6.6 | 0.313 |
Model adjusted for race, age, sex, T stage, nodal disease, distant metastases, smoking, alcohol use, education, insurance status, and income
1.4. Discussion
This is the first population-based study that confirms worse HPV-associated OPSCC survival outcomes in black patients across a range of adjustment sets incorporating demographic, clinical, and individual-level SES variables. It has previously been documented that racial differences in SES and access to care are significant determinants of head and neck cancer disparities.11–14,26,27 In OPSCC, racial differences in HPV tumor-status have been shown to contribute to the survival disparity.18,28 However, the relative contribution of HPV-status, tobacco use, alcohol use, treatment, and SES to racial disparities in OPSCC has not been determined. Our analysis with sequential adjustment sets demonstrates that racial differences in SES contributes to some but not all of the disparity.
Our findings build upon the growing evidence in current literature for the presence of racial disparities in OPSCC. In a large database analysis of OPSCC stratified by HPV-status, Faraji et al. found that there was a weak but non-significant trend towards worse overall survival (OS) among black patients with HPV-associated OPSCC after adjusting for age, sex, race, year of diagnosis, insurance status, income, education, rural residence, facility region, TNM stage, Charlson Deyo score, and treatment.29 A recent analysis of the SEER database found that among patients with HPV-associated OPSCC, black patients had significantly worse cancer-specific mortality than white patients even after adjusting for county-level indicators of SES.30 In another study, no racial difference in OS was found when controlling for treatment received in the Veteran’s Affairs medical system.19 It is possible that the more homogenous care afforded by the VA system could have mitigated some of the racial disparity attributable to differences in SES and access to care.
There may be several explanations for the persistence of the racial disparity in OS after adjustment for clinical and socioeconomic factors. First, unmeasured confounders in socioeconomic factors, physician and system factors, and access to care may exist. We found that black patients were more likely to have a low income compared to white patients, but our sample lacked the power to adjust for other variables such as frequency of primary care visits or routine dental visits. Studies have found that patients lacking routine dental visits are diagnosed at more advanced stages of head and neck cancer,31–33 although it is unknown if this pattern varies by race. In the past, racial disparities were largely attributed to genetic differences, but it is now recognized that race is a complex social construct and genetic factors are not likely to integrate with socially-defined racial groups as previously thought.34
Our study has several limitations. First, our study population had a small number of black patients with HPV-associated OPSCC. It should be noted that this is a limitation nationally, thereby limiting precise estimation of differences in this study population. Also, p16 testing was not routinely performed at the time of data collection for this study so our sample likely underestimates the true number of HPV-associated OPSCC patients in CHANCE. Given the small sample size of our study, it is important to recognize that some of the non-significant findings may be due to lack of statistical power rather than a true non-effect. Efforts are being undertaken to combine databases to increase the sample size of black patients with HPV-associated OPSCC for future validation studies. Another limitation is that the CHANCE database did not collect data on patient comorbidities, which may confound the relationship between race and OS. Disease specific mortality was not included in the analysis due to a lack of data on the specific cause of death for many of the CHANCE patients.
Our findings may have implications for cancer treatment and future research directions. There is strong evidence to support that patients with HPV-associated OPSCC have improved treatment response and survival outcomes compared to patients with HPV-negative disease.35 These findings have led to efforts to de-intensify treatment with the goal of alleviating therapy-related morbidity and mortality. Our results suggest that black patients with HPV-associated OPSCC may have worse outcomes despite their HPV-positive tumor status, and therefore, may not receive the same benefits from treatment deintensification. It is important to note that in our sample, we found no differences by race with regards to treatment type or number of treatments modalities received. Future de-intensification trials should closely monitor survival outcomes by race to ensure that this disparity is not being propagated.
Conclusions
There is a well-established correlation between race and survival outcomes in head and neck cancer. This population-based study demonstrated that the black versus white racial disparity in overall survival for HPV-associated OPSCC is only partially mediated by differences in SES. The persistence of the disparity after adjustment for demographic, clinical, and SES variables suggests the contribution of unmeasured confounders. Future research should seek to elucidate these determinants in order to fully address the racial disparity.
Acknowledgments:
This study was also made possible by the help of Paul Brennan, Devasena Anantharaman, and Behnoush Abedi-Ardekani from the International Agency for Research on Cancer (IARC), who helped with the creation of the CHANCE database. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization.
Funding: This work was supported in part by the US National Institutes of Health (NIH), National Cancer Institute (NCI) [R01- CA90731-01; R01- CA211939-03; CA233333-01; 2T32CA009330-21-26], National Institute of Dental and Craniofacial Research [DE025712-3] and National Institute of Environmental Health Sciences (NIEHS) P30ES010126]
Footnotes
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