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Occurrence of Cancer Among People With Mental Health Claims in an Insured Population

From the Departments of Psychiatry (C.P.C., R.N.) and Internal Medicine (C.P.C., B.N.D.), Indiana University School of Medicine, Indianapolis, IN; the Regenstrief Institute, Indianapolis, IN (C.P.C., B.N.D.); the Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, SC (R.F.W.); the Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA (L.J.); and Health Services Research and Development, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (B.N.D.).

Address correspondence and reprint requests to Caroline P. Carney, Regenstrief Institute, Indiana University School of Medicine, 1050 Wishard Blvd., RG6, Indianapolis, IN 46202-2872. E-mail: cdoebbeling{at}regenstrief.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION APPENDIX. ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVE: The objective of this research is to determine whether people with mental disorders are at increased risk for the subsequent development of malignancies compared with people without mental disorders.

METHODS: This is a retrospective cohort study of administrative claims data. The study population included 722,139 adults who filed at least one medical claim from 1989 to 1993. The mental disorder cohort included people with a) one psychiatric hospitalization, b) one outpatient psychiatrist visit, or c) two outpatient mental health claims occurring at least 6 months before a cancer claim. The controls were subjects filing claims for medical services who had no mental health visits. We calculated age-stratified odds ratios (ORs) for development of malignancy.

RESULTS: People with mental disorders were no more or less likely to develop a malignancy than those without after adjusting for age (women: OR, 1.03; 95% confidence interval [CI], 0.95–1.12; men: OR, 1.10; 95% CI, 0.97–1.24). People with mental disorders, however, developed cancer at younger ages and had increased odds of primary central nervous system tumors (women: OR, 2.12; 95% CI, 1.40–3.21; men: OR, 2.09; 95% CI, 1.22–3.59) and respiratory system cancers (women: OR, 1.57; 95% CI, 1.13–2.19; men: OR, 1.52; 95% CI, 1.09–2.12).

CONCLUSIONS: Insured people with mental disorder claims had an increased risk of certain malignancies and developed malignancies at younger ages. The increased odds of respiratory tumors are likely secondary to increased rates of smoking among people with mental disorders and support use of smoking cessation interventions in this population. The increased odds for brain tumors may reflect only the early presence of mental symptoms, or a true association between the two conditions. Further study of these findings is mandated.

Key Words: cancer, • mental illness, • claims data, • malignancy, • depression.

Abbreviations: SIR = standardized incidence ratio;; OR = odds ratio;; CI = confidence interval;; ICD-9 = International Classification of Disease Volume 9;; SEER = Surveillance Epidemiology and End Result.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION APPENDIX. ACKNOWLEDGMENTS REFERENCES

 
"Melancholic women are more prone to cancer than those of sanguine temperament." —Galen

The relationship between mental and physical disorders has long been of interest to clinicians and epidemiologists. The National Institute of Mental Health recently issued a call for research directed at the study of medical and psychiatric comorbidity (1). People with mental disorders may be at higher risk for conditions such as cancer because of high rates of smoking and alcohol abuse (2–9). That antidepressant and neuroleptic medications contribute to the development of malignancies is disputed (10–18). Psychiatric patients may have limited access to preventive medical services and consequently may be at greater risk for delay in diagnosis or treatment of malignancy (19–21).

In recent years, studies evaluating the association between mental disorders and cancer have mostly focused on two conditions: schizophrenia and depression. Schizophrenia has long been thought to have a protective effect, whereas depression has been thought to predispose to malignancy (22–28). However, the findings regarding both mental conditions are inconsistent.

Noteworthy studies evaluating cancer incidence and prevalence in patients with schizophrenia have been published recently. Gulbinat et al. (29) investigated the comorbidity between cancer and schizophrenia at three international sites (combined N = 16,236). No conclusions could be drawn about whether this mental disorder reduced cancer mortality, because no consistent pattern of increased or decreased cancer risk was found. Mortensen (30) studied the occurrence of cancer in first-admitted schizophrenic patients from 1970 to 1987 (total N = 9156). The standardized incidence ratios (SIRs) were lower for both men and women, even when controlling for tobacco use. Relying on death records and the 1986 National Mortality Followback Survey (N = 43,274), Dembling et al. (31) showed a decreased odds of cancer (odds ratio [OR], 0.59) in schizophrenics after controlling for age, smoking, sex, and hospitalization in the year before death. Lichterman et al. (32) studied hospital discharge and pension registers (446,653 person-years) linked to the Finnish Cancer Registry. Overall, men and women with schizophrenia were no more or less likely than people without schizophrenia to develop malignancies (men: SIR, 1.25; 95% confidence interval [CI], 1.11–1.38; women: SIR, 1.12; 95% CI, 1.01–1.22). With respect to particular malignancies, schizophrenic patients were twice as likely to develop lung cancer, but no more likely than the general population to develop breast cancer.

Several studies have evaluated the risk for cancer in people with depression. Generally, the studies published in the last decade do not support an association between the two conditions (5,22–26,28,31,33–46). Penninx et al. (25) suggested that chronic, severe depression predicted cancer in people older than 71 years (N = 4825). Although a recent Epidemiological Catchment Area follow-up study (N = 3109) showed that neither major depression (risk ratio [RR], 1.0; 95% CI, 0.5–2.1) nor dysphoric episode (RR, 1.3; CI, 0.9–1.9) were associated with an overall increased risk of cancer, women with major depression were found to have an increased risk for breast cancer (RR, 3.8; 95% CI, 1.0–14.2; 40). The increase in tobacco-related malignancies in people with depression has been attributed to higher tobacco use among the patients, but not to the depression itself (28,43).

Finally, a record linkage study of users of mental health services in Western Australia found that the overall cancer incidence did not differ between these people (N = 172,932) and the general population. However, the case fatality rate from cancer was greater in users of mental health services (19). Although other studies have evaluated the relationships among mental disorders, cancer, and mortality, most are limited by cross-sectional design, or by analyses calculating proportionate, not standardized, mortality (36,47).

These studies provide intriguing and sometimes conflicting results. With the exception of the Australian study, all focused on cancer risk in people with either schizophrenia or depression. Whether an association between mental illness and cancer occurs in the general population remains unknown. The question is important. If an increased cancer risk were to be found, clinical preventive services should target those with psychiatric disorders. If a decreased risk were found, efforts should be made to determine the reasons in a population that may actually have a greater risk factor burden.

Given that no mental health registries exist per se in the United States, longitudinal insurance claims data may serve as a proxy for such a mental health registry, especially if the insured population remains relatively stable (48,49). We hypothesize that people with psychiatric conditions, because of lifestyle factors such as increased tobacco and alcohol use, have higher rates of malignancy. By analyzing insurance claims data, we studied the cancer incidence of insured Midwesterners with and without mental illness. The overall findings for cancer incidence are reported in this article.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION APPENDIX. ACKNOWLEDGMENTS REFERENCES

 
The University of Iowa Institutional Review Board approved the study.

Data Source
The data source is a 100% sample of Wellmark Blue Cross/Blue Shield of Iowa and South Dakota inpatient and outpatient provider and administrative claims data from January 1, 1989, through December 31, 1993. The data source includes all Common Procedural Terminology codes and International Classification of Disease Volume 9 (ICD-9) codes for claims made by all providers. The claims data provide visit and procedural information on the >83% of enrolled members who filed claims during the specified interval. The covered population remained relatively stable, because two thirds of people in each cohort who filed claims in 1989 also filed claims in 1993.

Subjects
Men and women 18 to 64 years old who were insured by Blue Cross/Blue Shield between 1989 and 1993 and filed one or more claims were analyzed. Race information for subjects was not available because it was not collected on the claims forms. However, United States 2000 census data demonstrate that the population in Iowa was composed of approximately 95% white people (50). The study population was nearly equally divided between urban (55%) and rural (45%) dwellers as defined by metropolitan statistical areas (50,51). Overall age of the groups was based on age at first claim of any type. Cancer age was based on age at incident cancer. People older than 64 years were excluded from this analysis given the low number of claims submitted by this population, likely the result of concomitant Medicare coverage. We excluded subjects younger than age 18 years because of expected low rates of psychiatric conditions and cancers.

Classification of Mental Disorders
Subjects were assigned to the mental disorder cohort by means of established criteria validated by Lurie et al. (52) for use with administrative claims data. To validate that subjects with psychiatric claims had been diagnosed with a mental disorder and were classified into the correct broad diagnostic category (eg, depressive disorders), they must have filed at least the following:

1. One ICD-9 code for a mental disorder in the first or second diagnostic position for an inpatient visit, or
   
2. Two outpatient mental health ICD-9 codes by any physician, or
   
3. One ICD-9 mental health claim made by a psychiatrist.
   

We linked these ICD-9 codes to DSM-IV for the classification of subjects (Appendix; 53). Subjects were assigned to diagnostic categories based on the first occurring mental disorder code. Each subject was counted only once. To lessen the likelihood that cancer was causing the mental disorder, subjects were required to meet the classification criteria a minimum of 6 months before any ICD-9–coded malignancy. Subjects with mental health codes first occurring after the diagnosis of a malignancy (N = 1118) were excluded from the analyses because the temporal relationship between the psychiatric condition and the malignancy was unclear.

Classification of Controls
The control population included patients who had no claims for mental disorders at any time during 1989 to 1993 but had claims for malignancies.

Classification of Malignancies
Codes from ICD-9 for malignant cancers based on the classification system used by the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) cancer registry were used to classify cancer cases (Appendix; 54). Patients with nonmelanoma skin cancers were not classified as having a malignancy unless they also had another primary malignancy. Subjects were categorized into SEER groups (eg, malignancies of the respiratory system) based on the first primary malignancy coded. Given the exclusion of secondary and metastatic cancers, all subjects had only a single type of malignancy. In situations in which a nonsense code was found (eg, woman with prostate cancer), the subject’s other claims were reviewed to categorize the person properly. Subjects were excluded if the claims history remained nonsensical or inconsistent after further assessment. Subjects whose first claim for cancer occurred within 6 months of the first identified medical visit were excluded from the analyses to avoid misclassification of prevalent malignancies. Again, subjects whose first mental health claim occurred within 6 months of the cancer diagnosis were also excluded to decrease the likelihood that the mental disorder was a direct effect of the cancer.

Length of Follow-up
Length of follow-up was calculated based on the number of months between the first and last claims of any type. Given that membership files were unavailable, it is impossible to know with certainty when a person lost insurance coverage. Therefore, the most conservative approach was to measure time between known claims.

Statistical Analysis
The incidence of primary malignancies in the mental disorder cohort was compared with the incidence of primary malignancies in the control cohort for both men and women. Rates were compared with ² tests for categorical variables and t tests for continuous variables. The Mantel-Haenszel estimator of the OR and its 95% CI were calculated to adjust for age. Subjects were assigned to age groups: 18 to 34, 35 to 49, and 50 to 64 years. Value for was set at 0.05, and all p values were two-tailed. All analyses were conducted with SAS version 8.2 (SAS System, Cary, NC; 55).

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION APPENDIX. ACKNOWLEDGMENTS REFERENCES

 
Demographics
Overall, 812,219 subjects filed claims during 1989 to 1993. After exclusions, 722,139 people age 18 to 64 were available for analyses (Table 1). Of these, 72,140 were assigned to the mental health cohort and 649,999 to the control cohort. Nearly two thirds of the mental health cohort was composed of women, compared with more than one half of the controls (61% vs. 55%; p < .0001; Table 1).

Cancer Experience
Slightly more subjects in the mental health cohort (N = 915; 1.3%) developed cancer compared with controls (N = 7678; 1.2%; p = .0406; ² = 4.1930; df = 1). Women in the mental health cohort were younger than control women at the time of their first cancer claim (47.0 ± 10.2 years vs. 49.9 ± 11.0 years; t = 6.49; p < .0001). Men in the mental health cohort were also younger at their first cancer claim (51.5 ± 10.3 years vs. 53.2 ± 10.8 years; t = 2.50; p = .0126).

No significant differences in overall incidence were found for subjects 18 to 34 years old or 50 to 64 years old of either sex. There was no significant difference in cancer incidence for women with and without mental disorders for subjects 35 to 49 years old. However, men with mental disorders in this age group more commonly had a later malignancy claim (0.83%) than those without mental disorders (0.60%; p = .004; ²= = 8.18; df = 1).

We next calculated age-adjusted ORs for the development of specific malignancies by sex (Table 2; Figure 1). Men with mental disorders did not have significantly lower odds than men without mental disorders for the development of any subsequent malignancy. However, men with mental disorders had higher odds for brain and central nervous system tumors (OR, 2.09; 95% CI, 1.22–3.59) and respiratory tumors (OR, 1.52; 95% CI, 1.09–2.12). Tumors of the oral cavity and pharynx approached significance (OR, 1.56; 95% CI, 0.97–2.50; Table 2). The markedly elevated ORs for Kaposi sarcoma in men with mental disorders are thought to be unreliable given the small number of cases.

View larger version (24K): [in this window] [in a new window]   Figure 1. Age-adjusted ORs and 95% CIs for incidence of malignancies among subjects with mental disorders compared with those without.

Temporal Relationship
To assess the temporal relationship between the first mental health claim and cancer claim, we examined the interval between the two claims. Recalling that subjects with the first mental disorder claim occurring within 6 months of the first cancer claim were excluded from the analysis, the median number of days between the first mental health claim and any malignancy was 658 days for women and 638 days for men. Because brain and respiratory malignancies occurred more frequently in the mental disorder cohort than in controls, we also calculated the median numbers of days between claims for these malignancies. For brain tumors, the intervals were 516 days for women and 491 days for men. For lung cancer, the median lengths of time between first mental health claim and first lung cancer claim were 819 days for women and 703 days for men.

Mental Disorders
To determine whether any particular category of mental illness occurred more frequently in those who developed malignancies, we compared the distribution of mental disorders in people who later filed cancer claims with those in the population who had mental disorders but did not file malignancy claims. For men and women with mental disorders who later developed a malignancy, mood disorders were the most common (men, 32%; women, 43%), followed by adjustment disorders (men, 22%; women, 23%). Anxiety disorders were more common among women than men (17% vs. 11%; Table 3) The distribution of mental disorders in men with cancer was not different from that in those without cancer. Although not statistically significant, mood disorders were slightly more common in this sample of women who later developed cancer than in women who did not. No other differences were noted for women (Table 3).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION APPENDIX. ACKNOWLEDGMENTS REFERENCES

Brain tumors were significantly elevated in both men and women with psychiatric conditions. The median length of time between psychiatric presentation and the first brain tumor claim was approximately 1.5 years for women and men. This implies that some brain tumors are present and causing mental symptoms well ahead of other neurological symptoms leading to diagnostic evaluations. Tumors exert effects on the brain through several mechanisms, including tumor site (eg, temporal lobe), increased intracranial pressure, nature of the tumor, seizure activity, and individual predisposition to psychiatric symptoms. Given these mechanisms, a wide variety of psychiatric symptoms may occur before the diagnosis of brain tumors (56,57). We cannot determine how benign tumors might have influenced these findings because these were not included in the malignant tumor cohorts. We would expect similar findings if the cause of mental symptoms was from a mass effect. These findings call for further investigation into the nature of the mental disorders occurring before tumor diagnosis, grouping of cases by time between mental symptoms and tumor diagnosis, and the type and physical location of the brain tumors. This work is reported elsewhere (58).

Given that tobacco use is increased among people with mental disorders, the findings of elevated odds for respiratory and oral cavity cancers was not surprising. As described, many of the studies showing decreased rates of lung cancer in people with mental disorders may have been confounded secondary to selection bias. Studies reporting increased rates of lung cancer among the depressed have shown that this is a function of tobacco use among the depressed (28,43). Whether schizophrenics had different rates of lung cancer than those without mental disorders in this population is not known. The overall number of people with either schizophrenia or schizoaffective disorder in the sample of people with mental disorders was less than 1% (N = 509). Because only seven of these people developed any malignancy, calculation of ORs may have been unreliable.

We might expect to see other tobacco-related malignancies increased as well. However, our system based on SEER classifications for grouping malignancies makes this difficult to determine. The grouping was necessary given the small number of people with mental illness and more rare cancers. For example, bladder cancer would have been overlooked in this grouping system as part of the greater category of urinary system malignancies.

The increased odds for leukemia and lymphoma in women subjects were not expected. Unlike the increases in brain and lung cancer, this finding did not hold true for men in this population. Lymphoma may have an insidious presentation, characterized by fatigue and malaise. Certainly these symptoms may be mistaken for depression, but the 6-month exclusions should have removed many such cases. These findings will need to be confirmed in other populations.

Several strengths of this study bear mentioning. Insurance claims data provide an objective source of data for people seeking medical care. The sizable population provided by our data adds weight to the findings. For instance, even when using the 6-month exclusionary criteria, we still identified 176 cases of women who had filed claims for mental disorders and later developed breast cancer. Small area variation is less likely to influence findings when the population under study resides in a large geographical area, includes a wide variety of workers and their significant others, and covers many socioeconomic strata. Importantly, these data functions as a registry for people seeking mental health care, data that are otherwise difficult, time-consuming, and costly to collect.

We used stringent selection criteria to assign subjects to the mental disorder cohort. These criteria provided a method for validating insurance claim diagnoses within broad mental disorder categories. Although not reported here, we also performed analyses including people with only a single mental health claim made by any provider before the first cancer claim. The results were nearly identical. We chose to exclude people with mental health claims made after the cancer diagnosis to ensure that the mental condition was not the result of the malignancy. By including all previous psychiatric conditions and not limiting our investigation to a specific disorder such as schizophrenia, the findings are generalizable to people seeking treatment for mental disturbances. This is important to consider when using administrative claims data given the criticism that psychiatric codes may not truly reflect a person’s actual diagnosis.

Cancer incidence generally increases with age, and differences in age between the cohorts could have influenced these findings. The ORs for specific malignancies reported here were adjusted for age to account for that influence. We report that both men and women with mental disorders developed cancer at significantly younger ages than controls (2 and 3 years, respectively), a finding not previously reported. Some cancers, such as breast cancer, are more aggressive in younger people. Our age finding may complement findings that suggest that a higher cancer case fatality rate occurs among people with mental disorders (19).

Women with mental disorders in our study had similar odds of developing breast cancer (OR, 0.89; 95% CI, 0.74–1.02). Other researchers have observed similar or higher rates of breast cancer among chronic psychiatric patients compared with people in the general population (11,16,28). A follow-up study of the Baltimore Epidemiological Catchment Area cohort showed an increase in breast cancer among women who previously had depression; however, the number of cases was small (40). Recent cohort studies, one of which controlled for psychosocial factors, found no increased risk of breast cancer among women with schizophrenia (59). This fueled speculation that a protective, not a predisposing, factor might be attributed to psychotropic medications. What remains unclear in much of the existing literature is the definition of breast cancer. Does the definition include in situ and invasive cancers, for instance? We specifically included only invasive breast cancer. As may also be true for colorectal cancer, lack of screening may lead to delayed detection of early stage cancers and to a lower incidence in women who had not undergone screening. Receipt of screening mammography has been observed to be high among women in our population (60). We are currently evaluating the mammography experience and rates of in situ diagnoses among the women in our study (61).

Several important limitations of research involving claims data warrant mention. The data reflect the experiences of people seeking health care and filing insurance claims. These data do not apply to well people who have not sought medical care or mentally ill people who have not sought medical care. Medical service delivery and prevalence and incidence of medical conditions cannot be measured in these groups, as would be true of any study involving claims or registry data (eg, Medicare). Although we can be reasonably certain that cancer claims are valid, the same may not be true for mental disorders (62). Psychiatric diagnoses such as depression are underdiagnosed by primary care providers and may be underrepresented in this population (48,52,63,64). We cannot ascertain how many control subjects had undiagnosed mental disorders. If some of the control subjects who later developed cancer were moved into the case group, higher rates of cancers among those with mental disorders might have been found. We took this into consideration by making our criteria less restrictive and also analyzing all subjects who had only one mental health claim (results not reported here). Even when adding these people to the mental health group, the overall odds of incident malignancies did not change.

We performed preliminary life-table analyses. However, because of lack of precision in censorship (eg, subject lost insurance or did not file a claim), we believe the reported method of using ORs was appropriate. Because our comparison group was composed of contemporaries without mental conditions, we elected not to calculate SIRs. The length of observation was similar between the two cohorts when considering length from first mental health claim to last claim in the cases compared with the first and last claim of any type for the controls. The proportion of each cohort with continuous coverage over the entire 5-year period was also similar. In fact, when considering the first claim of any type, people with mental disorders were actually followed for a longer period, allowing for the possibility that this increased length of time contributed additional at-risk time for the development of a malignancy. Consequently, it is unlikely that people with mental disorders were disproportionately lost to follow-up or developed malignancies that were not counted. Because many of the psychiatric conditions included in this study are chronic and may have been present in people before the first insurance claim in this database, the appropriate length of follow-up is difficult to determine.

Finally, misclassification bias may have occurred. For example, claims for cancers diagnosed before 1989 may have appeared again, but only after a mental health claim was noted. People with psychiatric conditions diagnosed before 1989, but not coded again until after the development of a cancer, would have been excluded. We have no reason to suspect that misclassification bias may have affected the two cohorts differently, and our exclusion criteria should have been protected from this effect.

These data represent citizens primarily residing in Iowa, South Dakota, and the surrounding states. Given the largely white composition of the populations of the Midwest, the data may not generalize to ethnic or urban populations. However, the findings should generalize to other privately insured Americans. During the 2000 census, nearly 80% of all Americans had some form of medical insurance, with the largest proportion—approximately 65%—covered with employer-based insurance such as Blue Cross/Blue Shield (50). Whether the results may be applicable to the chronically mentally ill must also be considered. These results may be less applicable to the uninsured chronically mentally ill who may have more social and health effects from the psychiatric conditions, who may have an increased risk factor burden, or who may lack access to health care.

The clinical implications of this study are important. If one assumes that people who filed mental health claims were treated with either psychotherapy or pharmacotherapy, the cancer outcome may have been affected by the treatment itself, or by increased access to medical care. The data also suggest that people presenting with new mental symptoms at times of life atypical for a new onset of a psychiatric condition should undergo evaluation for the presence of a brain tumor. Both mental health workers and primary care providers should stress smoking cessation programs.

These data provide the basis for further research. For instance, the study could be repeated using Medicare data to study the elderly population, in which a higher incidence of cancer is found, or Medicaid populations including the chronically, seriously mentally ill. Our further work focuses on studying individual malignancies in greater depth. For instance, by linking these data with the National Cancer Institute’s SEER cancer registry data, we are able to add cancer stage and initial treatment. Thus, we will be able to determine whether patients with psychiatric disorders have more advanced tumors than people without mental conditions. Additionally, we have undertaken study of receipt of preventive medical services before cancer diagnosis in these patients. This work is the first of many steps in understanding mental health and cancer comorbidity in insured Americans.Table

	APPENDIX.

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION APPENDIX. ACKNOWLEDGMENTS REFERENCES

	ACKNOWLEDGMENTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION APPENDIX. ACKNOWLEDGMENTS REFERENCES

 
This study was supported by the American Cancer Society’s Seed Grant program and National Institute of Mental Health grant K08 MH01932 to 01A1 Epidemiology of Cancer and Mental Illness in Rural Areas.

The authors acknowledge the support of Dr. Sheila Riggs, Vice President of Healthcare Measurement and Reporting, Wellmark Blue Cross/Blue Shield of Iowa and South Dakota.

Received for publication October 29, 2003.

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TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION APPENDIX. ACKNOWLEDGMENTS REFERENCES

 

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