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Am J Epidemiol. Jan 1, 2009; 169(1): 41–53.
Published online Nov 10, 2008. doi:  10.1093/aje/kwn289
PMCID: PMC2720704

Study of Nevi in Children (SONIC): Baseline Findings and Predictors of Nevus Count

Abstract

The authors report baseline findings and predictors of nevus count (log total nevi) at the completion of year 1 (2004) of the first known population-based, prospective study of nevi in a US cohort of children. Overall, 64% (n = 443/691) of grade 5 students and their parents in Framingham, Massachusetts, completed surveys and underwent digital photography. Total nevus count was associated with skin and hair color and tendency to burn, as measured by a sun sensitivity index. In multivariate analyses, male gender (rate ratio (RR) = 1.38, 95% confidence interval (CI): 1.22, 1.55; P < 0.0001), spending 5–6 weekly hours outdoors between 10 AM and 4 PM (RR = 1.13, 95% CI: 1.00, 1.28; P = 0.051), getting a painful sunburn once (RR = 1.24, 95% CI: 0.98, 1.57; P = 0.073) and at least twice (RR = 1.34, 95% CI: 0.99, 1.82; P = 0.061), and wearing a shirt at the beach or pool rarely (RR = 1.29, 95% CI: 1.08, 1.54; P = 0.005), sometimes (RR = 1.26, 95% CI: 1.01, 1.57; P = 0.041), and often and always (RR = 1.32, 95% CI: 1.13, 1.54; P = 0.001) were associated with increased number of nevi. Identifying factors that predict the development of nevi will improve primary prevention efforts during early life.

Keywords: adolescent, child, environmental exposure, longitudinal studies, melanoma, nevus, nevus, pigmented, sunburn

The incidence of melanoma continues to rise rapidly, and melanoma mortality also continues to rise (1975–2003), albeit less precipitously (1). It is estimated that the number of new melanoma cases for 2008 will be 62,480, with an associated 8,420 deaths (1). The majority of the increase in melanoma incidence is attributable to one histogenic subtype—superficial spreading melanoma (1, 2). Nevi are potential precursors of melanoma and are among the most important known risk factors for the disease (38). The etiologic fraction of melanoma attributable to a high-risk nevus phenotype (i.e., large numbers of moles and/or the presence of atypical/dysplastic nevi) may exceed 50%, and the etiologic fraction associated with nevi as precursor lesions may be as high as 70% (9, 10).

Current knowledge of the evolution of nevi has been largely derived from cross-sectional studies, and these studies suggest that adolescence is an important time of life for the formation and evolution of nevi (1128). Many of these studies distinguish between common acquired and atypical (dysplastic) nevi. Common acquired nevi by definition are absent at birth, are often present in the early years of childhood, and are present in greater numbers in early to midlife (29). They predominate on sun-exposed skin above the waist. It is generally held that the common acquired nevus undergoes a predictable evolution over a period of years or decades. Initially, it appears as a tiny pinpoint macule (1–2 mm in diameter, uniformly tan or brown but occasionally black), which gradually enlarges to a maximal size of 4–6 mm (29, 30). Atypical nevi, the strongest indicator of melanoma risk (58), undergo clinically morphologic changes such as asymmetry, irregular borders, and color variation (31). Estimates of the incidence of atypical nevi in the US population range from 5% to 53% (31). Common and atypical nevi are both independent risk factors for melanoma (4).

Cross-sectional and longitudinal studies consistently demonstrate that nevi increase in number with age during childhood and adolescence and that sun exposure is an important correlate of the development of nevi and melanoma (35). Studies have also shown that constitutional factors, such as hair, eye, and skin color, are associated with the number of nevi (11, 1315, 1923, 2628, 3235).

It is important to understand the relation of sun exposure and phenotype with nevi because of the strong link between nevi and melanoma. Furthermore, understanding predictors of nevus count in children and adolescents will allow for more accurate risk assessment and melanoma prevention.

This ongoing study, the Study of Nevi in Children (SONIC), provides data on the first known population-based, longitudinal study of nevi in a US cohort of children during preadolescence in Framingham, Massachusetts. The overall objective of the study is to document the natural history of nevi in early adolescence by using digital photography and assess associations of sun-exposure and sun-protection behaviors and phenotype with the prevalence and progression of nevi over a 4-year follow-up. In this paper, we report on baseline findings and predictors of nevus count at the completion of year 1 data collection, 2004. On the basis of the characteristics of the population at baseline described here and follow-up of this cohort, it can be expected that the SONIC study will provide further understanding of the associations of genotype, phenotype, and sun exposure with the evolution of individual nevi.

MATERIALS AND METHODS

Student/parent recruitment and baseline survey

The study was conducted among children and their parents from the Framingham, Massachusetts, school system. The study was approved by the institutional review board at Boston University. We identified fifth-grade classrooms from 8 public and 2 parochial schools in Framingham. The study was planned and implemented as previously described (36). The study timetable is presented in Figure 1.

Figure 1.
Timetable and data collection for a study of nevi in children, Framingham, Massachusetts, 2004. Originally published on page 314 of Geller AC, Oliveria SA, Bishop M, Buckminster M, Brooks KR, Halpern AC. Study of health outcomes in school children: key ...

A study description, consent and assent forms, and surveys were mailed to the families of 691 fifth-grade students from the 10 schools, requesting their participation. Children and their parents were asked to complete a self-administered survey. Follow-up telephone calls were conducted 2 weeks after the initial mailing. The surveys included questions on demographics, phenotype (skin type, eye and hair color), sun sensitivity, sun exposure, sun-protection practices including use of hats and sunscreen, limiting time in the sun, and frequency of sunburns. The parent survey included questions about the child's sun-protection practices, sun exposure, and family history of cancer as well as information about the child's other parent (age, skin type, hair color, and ethnicity).

Skin examination and photography process

Skin examination and digital photography were performed in concert with mandatory screening examinations for scoliosis conducted annually in Massachusetts for children in grades 5–9. The examination was limited to the back and included digital photography for as many as 5 index nevi (4 back nevi and 1 facial nevus). Immediately following the scoliosis examination, the student underwent a brief visual examination by a trained nurse to assess hair, eye, and skin color. A standardized overview digital photograph of the back and close-up digital photography of the largest nevus on the upper back and lower back (if present) was performed. A random nevus from the upper and lower back (if present) was selected for photography. The upper back was defined as the area from the nape of the neck to the acromion processes to the level of lower tips of the scapulae. The lower back was defined as the area bordered by the lower tips of the scapulae superiorly and the posterior iliac crests inferiorly. All photography was performed with standardized photographic equipment (Phase One P25 Camera Back, Hasselblad 503w Camera System, Canfield Scientific, Inc. 1kWatt Studio Flash System) provided by Canfield Scientific, Inc. (Fairfield, New Jersey). The system permitted consistent color rendition calibrated to fiducial markers (as a fixed basis for comparison) within the images and allowed for efficient archiving of all images in a database.

Assessment of total back nevus count and presence of freckling

Total back nevus count and back freckling were determined independently by 2 study dermatologists. Two transparent reference lines were superimposed on each overview back image to demarcate 4 back quadrants. Each quadrant was enlarged 100% for evaluation. The reviewers located and digitally tagged each nevus. Total back nevus count was tallied as the sum of the 4 quadrants for each student. On the basis of work by other investigators (22, 37), we used methods that were accurate and feasible for the assessment of freckling. A visual scale depicting 4 levels of freckling (none, mild, moderate, and severe) was used to categorize each student. Because of potential misclassification of nevi as freckles, nevus counts for students with back freckling were validated by a second study dermatologist. We utilized a 2-mm cutpoint for determining a nevus versus a freckle (22, 37). Most studies have used a diameter of 2 mm as the lower size cutoff for the assessment of nevi to avoid the difficulty of distinguishing smaller lesions from freckles.

In our pilot study (38), we confirmed our ability to consistently assess 2-mm nevi on overview photographs. Clinically, freckles occur on only sun-exposed areas of the body; are well demarcated; can be round, oval, or irregular in shape; and are usually 1–3 mm in diameter (31). Compared with nevi, freckles are generally lighter in color, are located on sun-exposed skin, and are responsive to solar exposure. Conversely, nevi may occur on any site of the body and are well-circumscribed round or ovoid lesions, generally measuring 2–6 mm in diameter. Comparisons were possible because each nevus was tagged on the digital image during the initial nevus count. Concordance was high for nevus counts in this random sample of 50 students (rho = 0.91), even in the presence of freckling. There was also a high level of agreement regarding the presence of freckling in a subset of 100 students (kappa = 0.75, based on a weighted kappa value for the 4 categories of freckling).

Statistical analyses

The goal of this analysis was to identify individual and behavioral characteristics associated with nevus phenotype, defined as the total number of nevi on each participant's back. The number of nevi was log transformed after adding a constant of 1 to account for those study subjects without any nevi (16), and it was used as the outcome in the analyses. The choice of log transformation was motivated by its established variance-stabilizing property. Skin color, hair color, and Fitzpatrick tendency to burn are known risk factors for melanoma; because of their inherent correlation, a continuous sun sensitivity index (SSI) score was derived as a weighted combination of these 3 characteristics for each participant (39). Briefly, skin color was given a weight of 0 for a person with light skin, with the weight progressively increasing in equal fractional increments to 1 for dark skin. Red hair color was given a weight of 0, and the weights increased in a similar manner to 1 for dark hair color. Weights of 0 or 1 were assigned to the presence or absence of tendency to burn, respectively. Finally, SSI was derived as the sum of these 3 weights, resulting in a continuous score between 0 and 3. A score of 0 indicates a sun-sensitive participant (light skin, light hair, and tendency to burn), whereas a score of 3 corresponds to a person not sensitive to the sun (dark skin, dark hair, and no tendency to burn).

SSI was treated as a continuous variable in the analyses, and its association with log total nevus count was discerned by using graphic methods. For the analysis, back freckling was dichotomized as either present (mild, moderate, or severe) or absent (none). Categorical responses were obtained for all questionnaire items, and each item was treated as a categorical variable in the analyses. Adjacent response categories for a question were combined when fewer than 10% of the students responded to a single category. Student responses to questionnaire items were used for the analysis, and missing student data were imputed with parent responses. Multiple imputation (40) was used to handle missing responses.

The generalized estimating equations approach was used to identify variables (individual and behavioral characteristics) significantly associated with log nevus counts, treating schools as clusters and an exchangeable working correlation matrix (i.e., correlation of nevus phenotypes between any pair of students within a cluster is the same, regardless of their covariates) (41). Univariate analyses of each variable, adjusted for the effect of SSI, were pursued initially in 2 ways. First, univariate analyses were carried out by treating the variables as categorical. Next, trend tests were performed to identify variables significantly associated with log nevus count. Variables with trend-test P values smaller than 0.20 were candidates for consideration in multivariate analyses. All variables showing univariate significance were considered in the multivariate analyses, including race and gender, and were treated as categorical variables. Variables with P values larger than 0.10 in the multivariate model were eliminated 1 at a time in a stepwise manner to arrive at a final model. Although only some sun-exposure (defined as spending time outdoors between 10 AM and 4 PM during the week) categories and none of the sunscreen-use categories were significantly associated with nevus count by this P-value criterion, these variables were retained in the multivariate model because of their widely hypothesized role as potential risk factors for melanoma in general and nevi in particular.

Using 0.10 as the P-value cutoff instead of the conventional significance level of 0.05 was motivated by the implicit assumption that nevus phenotype is a heterogeneous trait. Furthermore, additional risk factors for nevi may remain to be examined, and some of the variables examined in this study may be associated with this trait through putative interactions. Consequently, choosing a higher significance level such as 0.10 and the hypothesized role of variables based on available literature provides a pragmatic modeling strategy. In this paper, several tables of univariate and multivariate analysis results report the rate ratios corresponding to the individual category of the variables considered in the model, which may be interpreted as the geometric mean of total nevus count for an individual in that category relative to the geometric mean in the baseline category when all other variables in the model are held constant. Corresponding 95% confidence intervals and P value are also reported. For example, a rate ratio of 1.5 for a category indicates that a student in that category has 50% more nevi than a student in the baseline category when all other variables are the same for the 2 students. All analyses were carried out by using Stata SE v9.1 software (Stata Corporation, College Station, Texas).

RESULTS

Participation rate

Of the 691 Framingham families with a fifth grader who were invited to participate in the study, 443 (64%) families consented to complete surveys and undergo a skin examination with digital photography. A total of 443 student image sets, 432 student surveys, and 424 parent surveys were obtained. These findings represent baseline results and predictors of nevus count at the completion of year 1 data collection.

Participant characteristics

Regarding nevi on the back, the 443 participating students had on average 8.4 (range: 0–119); 33 students had none, 196 students had 1−5, 94 students had 6–10, 61 students had 11–15, and 59 students had more than 15. No atypical nevi were observed. Characteristics of the students and parents are detailed in Table 1. Variables and weights for skin color, hair color, and tendency to burn and the derivation of the SSI index are presented in Table 2.

Table 1.
Characteristics of the Student and Parent Population in a Study of Nevi in Children, Framingham, Massachusetts, 2004a
Table 2.
Variables and Weightsa Used to Derive the Sun Sensitivity Index in a Study of Nevi in Children, Framingham, Massachusetts, 2004

Predictors of nevus phenotype

Figure 2 shows the relation between SSI and log total nevus count. The results of modeling demonstrated a quadratic relation and suggested that, in general, nevus count decreases as SSI increases. Based on these findings, linear and quadratic effects for SSI were included in all subsequent models.

Figure 2.
Relation between sun sensitivity index and log total nevus count in a study of nevi in children, Framingham, Massachusetts, 2004. Sun sensitivity index score was derived as a weighted combination of skin color, hair color, and Fitzpatrick tendency to ...

In a univariate analysis of back freckling, presence of back freckling was associated with a rate ratio of 1.79 (95% confidence interval for the rate ratio: 1.38, 2.32; P < 0.0001). Table 3 presents the univariate analyses of back freckling, sun-exposure variables, and log total nevus count, adjusted for the linear and quadratic effect of SSI. Table 4 provides the sun-protection variables that were significantly associated with total nevus count.

Table 3.
Univariate Analyses of Back Freckling, Sun-Exposure Variables, and Log Total Nevus Count, Adjusted for the Linear and Quadratic Effect of Sun Sensitivity Index, in a Study of Nevi in Children, Framingham, Massachusetts, 2004
Table 4.
Univariate Analyses of Back Freckling, Sun-Protection Variables, and Log Total Nevus Count, Adjusted for the Linear and Quadratic Effect of Sun Sensitivity Index, in a Study of Nevi in Children, Framingham, Massachusetts, 2004

The results of the multivariate model are given in Table 5.

Table 5.
Multivariate Model of Sun-Exposure and Sun-Protection Variables and Log Total Nevus Count, Adjusted for the Quadratic Effect of Sun Sensitivity Index, Ethnicity, and Gender, in a Study of Nevi in Children, Framingham, Massachusetts, 2004

DISCUSSION

In this paper, we report baseline results of the first known population-based, prospective study of nevi in a US cohort of children that documents the natural history of nevi using digital photography and assesses associations of phenotype, sun-exposure, and sun-protective behaviors with the prevalence and progression of nevi over a 4-year follow-up. Our results pertain to baseline findings and predictors of nevus count at the completion of year 1 data collection.

The study was conducted among children and their parents from the Framingham, Massachusetts, school system. This site was chosen because it provides a natural setting for long-term observational studies of children. Specifically, the school system 1) offers a cohort with a racial/ethnic mix similar to that of the US population (in the cohort, 70.0% of the children are white, 20.5% are nonwhite Hispanic, 4.3% are black/African American, and 5.2% are Asian American and other; the 2000 US census estimated that 63% of children aged 10–14 years are white, 17% are nonwhite Hispanic, 16% are black/African American, and 4% are Asian American and other) (42); 2) has successfully participated in large-scale health studies including a pilot of this study (38); and 3) has an excellent infrastructure for performing annual scoliosis examinations, which was crucial to implementing this study (36).

In our study, male students had 38% more nevi than females did. Other studies have suggested that male children have more nevi than female children (15). In an analysis of nevi in 2,552 Australian schoolchildren aged 5–14 years, males had more nevi at all ages than did females; median total-body nevus counts ranged from 40 at 5 years of age to 96 at 14 years of age in females, and from 51 to 120 in males, respectively (15). The results of our study show that total nevus count is associated with skin and hair color and tendency to burn, as measured by an index for sun sensitivity (SSI). Students with dark skin, dark hair, and no tendency to burn were less likely to have nevi. We also observed a small group of students with light skin, light hair, and tendency to burn who had few nevi. The presence of back freckling was also positively associated with nevus count. These findings are consistent with those of previous longitudinal and cross-sectional studies (13, 15, 23, 25, 26, 33, 34, 4347).

In multivariate analyses, male gender, hours spent in the sun, number of painful sunburns, wearing a shirt or hat, back freckling, and SSI were associated with increased number of nevi. Hours spent in the sun, as a measure of cumulative sun exposure, was associated with an increased number of nevi. This finding is in agreement with other studies (16, 33, 48). Results from previous studies on painful sunburning have shown inconsistent results, with some studies reporting a positive association while others not demonstrating this effect (13, 14, 25, 33, 44, 45, 47, 4951).

We assessed sun-protective behaviors, including using sunscreen and wearing protective clothing. Our results for wearing protective clothing were unexpected and are contradictory to those from other studies in which children with high nevus counts were less likely to practice sun-protective behaviors. It is possible that children's T-shirts worn at the beach do not protect enough against ultraviolet rays when exposed to intense sun or that the shirts do not protect all of the skin, or both, thus exposing children to burns and possibly new moles. In a study by English et al. (16), children whose backs were covered least often when outdoors had the most nevi. In other studies (33, 52), wearing clothing has been associated with fewer nevi. In our study, sunscreen use was interrogated with multiple questionnaire items including use of sunscreen on the face and back when outdoors and by the pool or beach. We elected to include sunscreen use in the multivariate model because of its hypothesized role as a protective factor against nevus counts. However, none of the sunscreen items were significantly associated with total back nevus counts. The rate ratio estimates of the significant risk factors did not change appreciably regardless of which sunscreen item was included in the multivariate model.

Table 5 illustrates the multivariate model including sunscreen use on the back when outdoors. Studies have been inconclusive, with a single randomized trial showing evidence of benefit and the prevention of nevi (20), while other studies have shown a positive association between sunscreen use and nevus count (26, 50, 5355). It has been proposed that these discrepant findings are due to confounding and/or measurement error. Male gender was associated with increased nevus count, after adjustment for potential confounding factors, which is consistent with other studies in which investigators have observed a higher number and density of nevi (13, 15, 23, 44, 50, 56, 57).

This analysis was cross-sectional and thus has inherent limitations related to the temporal sequence of exposures and outcome. The longitudinal design of this study will enable future analyses to assess risk factors for the development of incident nevi and address the temporal relation between exposures and nevus phenotype. This study was limited to nevi on the back as the anatomic focus. Selection of the back was based on both logistic and epidemiologic considerations (11, 15). The existing school infrastructure for administering scoliosis examinations, along with the efficiency of restricting the study to the skin of the back, was anticipated to result in very high participation rates and excellent data quality, as demonstrated in our pilot study (38).

Other logistic considerations in selecting the back were its relatively flat surface, which lends itself to photography studies. The utility and efficiency of restricting our study to the back are supported by several epidemiologic studies: English et al. (15, 58) demonstrated the least interobserver variation for nevus counts of the back relative to other anatomic sites, as well as excellent correlation between back nevus counts from photographs and those from direct examination. Autier et al. (11) demonstrated a strong correlation between back and total nevus counts and recognized the phenotype of back nevi as an excellent marker of melanoma risk. Uncontrolled confounding is also a potential source of error in this study related to factors associated with sun exposure, sun protection, and nevus phenotype. The potential for misclassification of important factors such as SSI is small because students underwent a brief visual examination to assess hair, eye, and skin color by a trained nurse, and tendency to burn was obtained by student self-report. Furthermore, these data were collected without knowledge of the outcome of interest, log mole count. Mole count was assessed without knowledge of the potential predictor variables.

Understanding the cause and development of nevi has important public health implications for primary and secondary prevention of melanoma. Public health campaigns and clinical efforts to reduce melanoma deaths currently target individuals with many nevi or apparently atypical nevi. Melanoma is very uncommon in early life, representing 1%–3% of all malignant tumors in people younger than 20 years of age (5964). Despite this rarity, recent evidence has indicated that melanoma is now occurring more frequently in children and adolescents (59, 60, 6371). The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute reported the incidence of malignant melanoma in children to be 1.3 per 1 million (72). The incidence of melanoma in children (aged <20 years) increased 2.9% (95% confidence interval: 2.1, 3.6) per year from 1973 to 2001 (70). However, the incidence of melanoma among children did not grow more than the incidence among people of other ages during this same time period. In fact, the 2.9% increase is consistent with the annual percentage increase found for persons of all ages in the same period.

Greater public and clinician attention to signs of early melanoma in persons of all ages is one important factor that contributes to this finding. Identification of factors that predict the development of multiple and atypical nevi will improve targeting of primary and secondary prevention efforts in early life. Because these factors may be apparent earlier in life, there is an opportunity to intervene when sun-protection efforts are more likely to succeed. With regard to secondary prevention of melanoma, recent efforts at early detection have intensified across all age groups, with an emphasis on the importance of change in a nevus as a sensitive marker of early curable disease. This emphasis has led to increasing nevus biopsies in adolescence. Understanding nevus evolution is critical to avoiding unnecessary biopsies in this age group.

In conclusion, results of our study suggest that numerous factors, both constitutional and environmental, affect nevus count. It is important to understand the heterogeneity of the relation between these factors and nevus phenotype. Assessment of the impact of sun-protective behaviors requires better measures and improved strategies for control of confounding. Future analyses based on the longitudinal data from this study will provide the opportunity to shed light on these important associations.

Acknowledgments

Author affiliations: Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (Susan A. Oliveria, Stephen W. Dusza, Maureen K. Heneghan, Allan C. Halpern); Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (Susan A. Oliveria, Jaya M. Satagopan); Department of Dermatology, Boston University, Boston, Massachusetts (Alan C. Geller); Dermatoepidemiology Unit, VA Medical Center, Providence, Rhode Island (Martin A. Weinstock); Department of Dermatology, Brown University, Providence, Rhode Island (Martin A. Weinstock); Department of Epidemiology, University of New Mexico, Albuquerque, New Mexico (Marianne Berwick); and School Health Services, Framingham Public Schools, Framingham, Massachusetts (Marilyn Bishop).

This research was supported by a grant provided by the National Institutes of Health (funding source R01AR049342).

The authors thank the teachers and staff of the Framingham School System who participated in this study.

Conflict of interest: none declared.

Glossary

Abbreviations

SONIC
Study of Nevi in Children
SSI
sun sensitivity index

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