Reproductive risk factors for breast cancer and association with novel breast density measurements among Hispanic, Black, and White women.

PURPOSE: There are differences in the distributions of breast cancer incidence and risk factors by race and ethnicity. Given the strong association between breast density and breast cancer, it is of interest describe racial and ethnic variation in the determinants of breast density. METHODS: We characterized racial and ethnic variation in reproductive history and several measures of breast density for Hispanic (n = 286), non-Hispanic Black (n = 255), and non-Hispanic White (n = 1694) women imaged at a single hospital. We quantified associations between reproductive factors and percent volumetric density (PVD), dense volume (DV), non-dense volume (NDV), and a novel measure of pixel intensity variation (V) using multivariable-adjusted linear regression, and tested for statistical heterogeneity by race and ethnicity. RESULTS: Reproductive factors most strongly associated with breast density were age at menarche, parity, and oral contraceptive use. Variation by race and ethnicity was most evident for the associations between reproductive factors and NDV (minimum p-heterogeneity:0.008) and V (minimum p-heterogeneity:0.004) and least evident for PVD (minimum p-heterogeneity:0.042) and DV (minimum p-heterogeneity:0.041). CONCLUSION: Reproductive choices, particularly those related to childbearing and oral contraceptive use, may contribute to racial and ethnic variation in breast density.

Association of Daily Alcohol Intake, Volumetric Breast Density, and Breast Cancer Risk.

High alcohol intake and breast density increase breast cancer (BC) risk, but their interrelationship is unknown. We examined whether volumetric density modifies and/or mediates the alcohol-BC association. BC cases (n = 2233) diagnosed from 2006 to 2013 in the San Francisco Bay area had screening mammograms 6 or more months before diagnosis; controls (n = 4562) were matched on age, mammogram date, race or ethnicity, facility, and mammography machine. Logistic regression was used to estimate alcohol-BC associations adjusted for age, body mass index, and menopause; interaction terms assessed modification. Percent mediation was quantified as the ratio of log (odds ratios [ORs]) from models with and without density measures. Alcohol consumption was associated with increased BC risk (2-sided P trend = .004), as were volumetric percent density (OR = 1.45 per SD, 95% confidence interval [CI] = 1.36 to 1.56) and dense volume (OR = 1.30, 95% CI = 1.24 to 1.37). Breast density did not modify the alcohol-BC association (2-sided P > .10 for all). Dense volume mediated 25.0% (95% CI = 5.5% to 44.4%) of the alcohol-BC association (2-sided P = .01), suggesting alcohol may partially increase BC risk by increasing fibroglandular tissue.

Early-Life and Adult Anthropometrics in Relation to Mammographic Image Intensity Variation in the Nurses' Health Studies.

BACKGROUND: The V measure captures grayscale intensity variation on a mammogram and is positively associated with breast cancer risk, independent of percent mammographic density (PMD), an established marker of breast cancer risk. We examined whether anthropometrics are associated with V, independent of PMD. METHODS: The analysis included 1,700 premenopausal and 1,947 postmenopausal women without breast cancer within the Nurses' Health Study (NHS) and NHSII. Participants recalled their body fatness at ages 5, 10, and 20 years using a 9-level pictogram (level 1: most lean) and reported weight at age 18 years, current adult weight, and adult height. V was estimated by calculating standard deviation of pixels on screening mammograms. Linear mixed models were used to estimate beta coefficients (ß) and 95% confidence intervals (CI) for the relationships between anthropometric measures and V, adjusting for confounders and PMD. RESULTS: V and PMD were positively correlated (Spearman r = 0.60). Higher average body fatness at ages 5 to 10 years (level ≥ 4.5 vs. 1) was significantly associated with lower V in premenopausal (ß = -0.32; 95% CI, -0.48 to -0.16) and postmenopausal (ß = -0.24; 95% CI, -0.37 to -0.10) women, independent of current body mass index (BMI) and PMD. Similar inverse associations were observed with average body fatness at ages 10 to 20 years and BMI at age 18 years. Current BMI was inversely associated with V, but the associations were largely attenuated after adjustment for PMD. Height was not associated with V. CONCLUSIONS: Our data suggest that early-life body fatness may reflect lifelong impact on breast tissue architecture beyond breast density. However, further studies are needed to confirm the results. IMPACT: This study highlights strong inverse associations of early-life adiposity with mammographic image intensity variation.

Radiologic Features of Small Pulmonary Nodules and Lung Cancer Risk in the National Lung Screening Trial: A Nested Case-Control Study.

Purpose To extract radiologic features from small pulmonary nodules (SPNs) that did not meet the original criteria for a positive screening test and identify features associated with lung cancer risk by using data and images from the National Lung Screening Trial (NLST). Materials and Methods Radiologic features in SPNs in baseline low-dose computed tomography (CT) screening studies that did not meet NLST criteria to be considered a positive screening examination were extracted. SPNs were identified for 73 incident case patients who were given a diagnosis of lung cancer at either the first or second follow-up screening study and for 157 control subjects who had undergone three consecutive negative screening studies. Multivariable logistic regression was used to assess the association between radiologic features and lung cancer risk. All statistical tests were two sided. Results Nine features were significantly different between case patients and control subjects. Backward elimination followed by bootstrap resampling identified a reduced model of highly informative radiologic features with an area under the receiver operating characteristic curve of 0.932 (95% confidence interval [CI]: 0.88, 0.96), a specificity of 92.38% (95% CI: 52.22%, 84.91%), and a sensitivity of 76.55% (95% CI: 87.50%, 95.35%) that included total emphysema score (odds ratio [OR] = 1.71; 95% CI: 1.39, 2.01), attachment to vessel (OR = 2.41; 95% CI: 0.99, 5.81), nodule location (OR = 3.25; 95% CI: 1.09, 8.55), border definition (OR = 7.56; 95% CI: 1.89, 30.8), and concavity (OR = 2.58; 95% CI: 0.89, 5.64). Conclusion A set of clinically relevant radiologic features were identified that that can be easily scored in the clinical setting and may be of use to determine lung cancer risk among participants with SPNs. © RSNA, 2017 Online supplemental material is available for this article.

Longitudinal Changes in Volumetric Breast Density with Tamoxifen and Aromatase Inhibitors.

Background: Reductions in breast density with tamoxifen and aromatase inhibitors may be an intermediate marker of treatment response. We compare changes in volumetric breast density among breast cancer cases using tamoxifen or aromatase inhibitors (AI) to untreated women without breast cancer.Methods: Breast cancer cases with a digital mammogram prior to diagnosis and after initiation of tamoxifen (n = 366) or AI (n = 403) and a sample of controls (n = 2170) were identified from the Mayo Clinic Mammography Practice and San Francisco Mammography Registry. Volumetric percent density (VPD) and dense breast volume (DV) were measured using Volpara (Matakina Technology) and Quantra (Hologic) software. Linear regression estimated the effect of treatment on annualized changes in density.Results: Premenopausal women using tamoxifen experienced annualized declines in VPD of 1.17% to 1.70% compared with 0.30% to 0.56% for controls and declines in DV of 7.43 to 15.13 cm3 compared with 0.28 to 0.63 cm3 in controls, for Volpara and Quantra, respectively. The greatest reductions were observed among women with ≥10% baseline density. Postmenopausal AI users had greater declines in VPD than controls (Volpara P = 0.02; Quantra P = 0.03), and reductions were greatest among women with ≥10% baseline density. Declines in VPD among postmenopausal women using tamoxifen were only statistically greater than controls when measured with Quantra.Conclusions: Automated software can detect volumetric breast density changes among women on tamoxifen and AI.Impact: If declines in volumetric density predict breast cancer outcomes, these measures may be used as interim prognostic indicators. Cancer Epidemiol Biomarkers Prev; 26(6); 930-7. ©2017 AACR.

Association Between Computed Tomographic Features and Kirsten Rat Sarcoma Viral Oncogene Mutations in Patients With Stage I Lung Adenocarcinoma and Their Prognostic Value.

BACKGROUND: We investigated the association between computed tomographic (CT) features and Kirsten rat sarcoma viral oncogene (KRAS) mutations in patients with stage I lung adenocarcinoma and their prognostic value. PATIENTS AND METHODS: A total of 79 patients with pathologic stage I lung adenocarcinoma, available KRAS mutational status, preoperative CT images available, and survival data were included in the present study. Seven CT features, including spiculation, concavity, ground-glass opacity, bubble-like lucency, air bronchogram, pleural retraction, and pleural attachment, were evaluated. The association among the clinical characteristics, CT features, and mutational status was analyzed using Student's t test, the χ(2) test or Fisher's exact test, and logistic regression. The association among CT features, mutational status, and overall survival was analyzed using Kaplan-Meier survival curves with the log-rank test and Cox proportional hazard regression. RESULTS: The prevalence of KRAS mutations was 41.77%. Spiculation was significantly associated with the presence of KRAS mutations (odds ratio, 2.99; 95% confidence interval [CI], 1.16-7.68). Although KRAS mutational status was not significantly associated with overall survival, the presence of pleural attachment was associated with an increased risk of death (hazard ratio, 2.46; 95% CI, 1.09-5.53). When analyzing KRAS mutational status and pleural attachment combined, patients with wild-type KRAS and no pleural attachment had significantly better survival than did those with wild-type KRAS and pleural attachment (P = .014). CONCLUSION: These data suggest that spiculation is associated with KRAS mutations and pleural attachment is associated with overall survival in patients with stage I lung adenocarcinoma. Combining the analysis of KRAS mutational status and CT features could better predict survival.

Semiquantitative Computed Tomography Characteristics for Lung Adenocarcinoma and Their Association With Lung Cancer Survival.

UNLABELLED: In this study we developed 25 computed tomography descriptors among 117 patients with lung adenocarcinoma to semiquantitatively assess their association with overall survival. Pleural attachment was significantly associated with an increased risk of death and texture was most important for distinguishing histological subtypes. This approach has the potential to support automated analyses and develop decision-support clinical tools. BACKGROUND: Computed tomography (CT) characteristics derived from noninvasive images that represent the entire tumor might have diagnostic and prognostic value. The purpose of this study was to assess the association of a standardized set of semiquantitative CT characteristics of lung adenocarcinoma with overall survival. PATIENTS AND METHODS: An initial set of CT descriptors was developed to semiquantitatively assess lung adenocarcinoma in patients (n = 117) who underwent resection. Survival analyses were used to determine the association between each characteristic and overall survival. Principle component analysis (PCA) was used to determine characteristics that might differentiate histological subtypes. RESULTS: Characteristics significantly associated with overall survival included pleural attachment (P < .001), air bronchogram (P = .03), and lymphadenopathy (P = .02). Multivariate analyses revealed pleural attachment was significantly associated with an increased risk of death overall (hazard ratio [HR], 3.21; 95% confidence interval [CI], 1.53-6.70) and among patients with lepidic predominant adenocarcinomas (HR, 5.85; 95% CI, 1.75-19.59), and lymphadenopathy was significantly associated with an increased risk of death among patients with adenocarcinomas without a predominant lepidic component (HR, 3.07; 95% CI, 1.09-8.70). A PCA model showed that texture (ground-glass opacity component) was most important for separating the 2 subtypes. CONCLUSION: A subset of the semiquantitative characteristics described herein has prognostic importance and provides the ability to distinguish between different histological subtypes of lung adenocarcinoma.

Automated Percentage of Breast Density Measurements for Full-field Digital Mammography Applications.

RATIONALE AND OBJECTIVES: Increased mammographic breast density is a significant risk factor for breast cancer. A reproducible, accurate, and automated breast density measurement is required for full-field digital mammography (FFDM) to support clinical applications. We evaluated a novel automated percentage of breast density measure (PDa) and made comparisons with the standard operator-assisted measure (PD) using FFDM data. METHODS: We used a nested breast cancer case-control study matched on age, year of mammogram and diagnosis with images acquired from a specific direct x-ray conversion FFDM technology. PDa was applied to the raw and clinical display (or processed) representation images. We evaluated the transformation (pixel mapping) of the raw image, giving a third representation (raw-transformed), to improve the PDa performance using differential evolution optimization. We applied PD to the raw and clinical display images as a standard for measurement comparison. Conditional logistic regression was used to estimate the odd ratios (ORs) for breast cancer with 95% confidence intervals (CI) for all measurements; analyses were adjusted for body mass index. PDa operates by evaluating signal-dependent noise (SDN), captured as local signal variation. Therefore, we characterized the SDN relationship to understand the PDa performance as a function of data representation and investigated a variation analysis of the transformation. RESULTS: The associations of the quartiles of operator-assisted PD with breast cancer were similar for the raw (OR: 1.00 [ref.]; 1.59 [95% CI, 0.93-2.70]; 1.70 [95% CI, 0.95-3.04]; 2.04 [95% CI, 1.13-3.67]) and clinical display (OR: 1.00 [ref.]; 1.31 [95% CI, 0.79-2.18]; 1.14 [95% CI, 0.65-1.98]; 1.95 [95% CI, 1.09-3.47]) images. PDa could not be assessed on the raw images without preprocessing. However, PDa had similar associations with breast cancer when assessed on 1) raw-transformed (OR: 1.00 [ref.]; 1.27 [95% CI, 0.74-2.19]; 1.86 [95% CI, 1.05-3.28]; 3.00 [95% CI, 1.67-5.38]) and 2) clinical display (OR: 1.00 [ref.]; 1.79 [95% CI, 1.04-3.11]; 1.61 [95% CI, 0.90-2.88]; 2.94 [95% CI, 1.66-5.19]) images. The SDN analysis showed that a nonlinear relationship between the mammographic signal and its variation (ie, the biomarker for the breast density) is required for PDa. Although variability in the transform influenced the respective PDa distribution, it did not affect the measurement's association with breast cancer. CONCLUSIONS: PDa assessed on either raw-transformed or clinical display images is a valid automated breast density measurement for a specific FFDM technology and compares well against PD. Further work is required for measurement generalization.

A comparison of calibration data from full field digital mammography units for breast density measurements.

BACKGROUND: Breast density is a significant breast cancer risk factor measured from mammograms. The most appropriate method for measuring breast density for risk applications is still under investigation. Calibration standardizes mammograms to account for acquisition technique differences prior to making breast density measurements. We evaluated whether a calibration methodology developed for an indirect x-ray conversion full field digital mammography (FFDM) technology applies to direct x-ray conversion FFDM systems. METHODS: Breast tissue equivalent (BTE) phantom images were used to establish calibration datasets for three similar direct x-ray conversion FFDM systems. The calibration dataset for each unit is a function of the target/filter combination, x-ray tube voltage, current × time (mAs), phantom height, and two detector fields of view (FOVs). Methods were investigated to reduce the amount of calibration data by restricting the height, mAs, and FOV sampling. Calibration accuracy was evaluated with mixture phantoms. We also compared both intra- and inter-system calibration characteristics and accuracy. RESULTS: Calibration methods developed previously apply to direct x-ray conversion systems with modification. Calibration accuracy was largely within the acceptable range of ± 4 standardized units from the ideal value over the entire acquisition parameter space for the direct conversion units. Acceptable calibration accuracy was maintained with a cubic-spline height interpolation, representing a modification to previous work. Calibration data is unit specific, can be acquired with the large FOV, and requires a minimum of one reference mAs sample. The mAs sampling, calibration accuracy, and the necessity for machine specific calibration data are common characteristics and in agreement with our previous work. CONCLUSION: The generality of our calibration approach was established under ideal conditions. Evaluation with patient data using breast cancer status as the endpoint is required to demonstrate that the approach produces a breast density measure associated with breast cancer.

Comparison of percent density from raw and processed full-field digital mammography data.

INTRODUCTION: Mammographic density has been established as a strong risk factor for breast cancer, primarily using digitized film mammograms. Full-field digital mammography (FFDM) is replacing film mammography, has different properties than film, and provides both raw and processed clinical display representation images. We evaluated and compared FFDM raw and processed breast density measures and their associations with breast cancer. METHODS: A case-control study of 180 cases and 180 controls matched by age, postmenopausal hormone use, and screening history was conducted. Mammograms were acquired from a General Electric Senographe 2000D FFDM unit. Percent density (PD) was assessed for each FFDM representation using the operator-assisted Cumulus method. Reproducibility within image type (n = 80) was assessed using Lin's concordance correlation coefficient (rc). Correlation of PD between image representations (n = 360) was evaluated using Pearson's correlation coefficient (r) on the continuous measures and the weighted kappa statistic (κ) for quartiles. Conditional logistic regression was used to estimate odds ratios (ORs) for the PD and breast cancer associations for both image representations with 95% confidence intervals. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminatory accuracy. RESULTS: Percent density from the two representations provided similar intra-reader reproducibility (rc= 0.92 for raw and rc= 0.87 for processed images) and was correlated (r = 0.82 and κ = 0.64). When controlling for body mass index, the associations of quartiles of PD with breast cancer and discriminatory accuracy were similar for the raw (OR: 1.0 (ref.), 2.6 (1.2 to 5.4), 3.1 (1.4 to 6.8), 4.7 (2.1 to 10.6); AUC = 0.63) and processed representations (OR: 1.0 (ref.), 2.2 (1.1 to 4.1), 2.2 (1.1 to 4.4), 3.1 (1.5 to 6.6); AUC = 0.64). CONCLUSIONS: Percent density measured with an operator-assisted method from raw and processed FFDM images is reproducible and correlated. Both percent density measures provide similar associations with breast cancer.

Survival analysis of patients with stage I non-small-cell lung cancer using clinical and DNA repair pathway expression variables.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality. Understanding patient attributes that enhance survival and predict recurrence is necessary to individualize treatment options. METHODS: Patients (N = 162) were dichotomized into favorable (n = 101) and unfavorable (n = 61) groups based on survival characteristics. Ku86 and poly(ADP-ribose) polymerase (PARP) expression measures were incorporated into the analyses. LR, Kaplan-Meier analysis, and Cox regression were used to investigate intervariable relationships and survival. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess associations. RESULTS: Sex (OR, 0.32; CI-0.14, 0.76), squamous cell carcinoma (SCC) (OR, 0.41; CI-0.17, 0.98), and recurrence (OR, 0.04; CI-0.01, 0.20) confer an unfavorable outcome with area under the receiver operating characteristic curve (Az) = 0.788. Patients with increased tumor grade (OR = 1.84; CI-1.06, 3.19) or increased Ku86 intensity (OR, 2.03; CI-1.08, 3.82) were more likely to be male individuals, and older patients (OR, 1.70; CI-(1.14, 2.52) were more likely to have SCC. Patients older than the median age (HR, 1.86; CI-1.11, 3.12), patients with SCC (HR, 1.78; CI-1.05, 3.01), patients with recurrence (HR, 4.16; CI-2.37, 7.31), and male patients (HR, 2.03; CI-1.20, 3.43) have a higher hazard. None of the DNA repair measures were associated with significant HRs. CONCLUSION: Clinical and pathologic factors that enhance and limit survival for patients with stage I NSCLC were quantified. The DNA repair measures showed little association. These findings are important given that certain clinical and pathologic features are related to better long-term survival outcome than others.

The influence of mammogram acquisition on the mammographic density and breast cancer association in the Mayo Mammography Health Study cohort.

INTRODUCTION: Mammographic density is a strong risk factor for breast cancer. Image acquisition technique varies across mammograms to limit radiation and produce a clinically useful image. We examined whether acquisition technique parameters at the time of mammography were associated with mammographic density and whether the acquisition parameters confounded the density and breast cancer association. METHODS: We examined this question within the Mayo Mammography Health Study (MMHS) cohort, comprised of 19,924 women (51.2% of eligible) seen in the Mayo Clinic mammography screening practice from 2003 to 2006. A case-cohort design, comprising 318 incident breast cancers diagnosed through December 2009 and a random subcohort of 2,259, was used to examine potential confounding of mammogram acquisition technique parameters (x-ray tube voltage peak (kVp), milliampere-seconds (mAs), thickness and compression force) on the density and breast cancer association. The Breast Imaging Reporting and Data System four-category tissue composition measure (BI-RADS) and percent density (PD) (Cumulus program) were estimated from screen-film mammograms at time of enrollment. Spearman correlation coefficients (r) and means (standard deviations) were used to examine the relationship of density measures with acquisition parameters. Hazard ratios (HR) and C-statistics were estimated using Cox proportional hazards regression, adjusting for age, menopausal status, body mass index and postmenopausal hormones. A change in the HR of at least 15% indicated confounding. RESULTS: Adjusted PD and BI-RADS density were associated with breast cancer (p-trends < 0.001), with a 3 to 4-fold increased risk in the extremely dense vs. fatty BI-RADS categories (HR: 3.0, 95% CI, 1.7 - 5.1) and the ≥ 25% vs. ≤ 5% PD categories (HR: 3.8, 95% CI, 2.5 - 5.9). Of the acquisition parameters, kVp was not correlated with PD (r = 0.04, p = 0.07). Although thickness (r = -0.27, p < 0.001), compression force (r = -0.16, p < 0.001), and mAs (r = -0.06, p = 0.008) were inversely correlated with PD, they did not confound the PD or BI-RADS associations with breast cancer and their inclusion did not improve discriminatory accuracy. Results were similar for associations of dense and non-dense area with breast cancer. CONCLUSIONS: We confirmed a strong association between mammographic density and breast cancer risk that was not confounded by mammogram acquisition technique.

A novel automated mammographic density measure and breast cancer risk.

BACKGROUND: Mammographic breast density is a strong breast cancer risk factor but is not used in the clinical setting, partly because of a lack of standardization and automation. We developed an automated and objective measurement of the grayscale value variation within a mammogram, evaluated its association with breast cancer, and compared its performance with that of percent density (PD). METHODS: Three clinic-based studies were included: a case-cohort study of 217 breast cancer case subjects and 2094 non-case subjects and two case-control studies comprising 928 case subjects and 1039 control subjects and 246 case subjects and 516 control subjects, respectively. Percent density was estimated from digitized mammograms using the computer-assisted Cumulus thresholding program, and variation was estimated from an automated algorithm. We estimated hazards ratios (HRs), odds ratios (ORs), the area under the receiver operating characteristic curve (AUC), and 95% confidence intervals (CIs) using Cox proportional hazards models for the cohort and logistic regression for case-control studies, with adjustment for age and body mass index. We performed a meta-analysis using random study effects to obtain pooled estimates of the associations between the two mammographic measures and breast cancer. All statistical tests were two-sided. RESULTS: The variation measure was statistically significantly associated with the risk of breast cancer in all three studies (highest vs lowest quartile: HR = 2.0 [95% CI = 1.3 to 3.1]; OR = 2.7 [95% CI = 2.1 to 3.6]; OR = 2.4 [95% CI = 1.4 to 3.9]; [corrected] all P (trend) < .001). [corrected]. The risk estimates and AUCs for the variation measure were similar to [corrected] those for percent density (AUCs for variation = 0.60-0.62 and [corrected] AUCs for percent density = 0.61-0.65). [corrected]. A meta-analysis of the three studies demonstrated similar associations [corrected] between variation and breast cancer (highest vs lowest quartile: RR = 1.8, 95% CI = 1.4 to 2.3) and [corrected] percent density and breast cancer (highest vs lowest quartile: RR = 2.3, 95% CI = 1.9 to 2.9). CONCLUSION: The association between the automated variation measure and the risk of breast cancer is at least as strong as that for percent density. Efforts to further evaluate and translate the variation measure to the clinical setting are warranted.

Perturbation and candidate analysis to combat overfitting of gene expression microarray data.

Analysis of gene expression microarray datasets presents the high risk of over-fitting (spurious patterns) because of their feature-rich but case-poor nature. This paper describes our ongoing efforts to develop a method to combat over-fitting and determine the strongest signal in the dataset. A GA-SVM hybrid along with Gaussian noise (manual noise gain) is used to discover feature sets of minimal size that accurately classifies the cases under cross-validation. Initial results on a colorectal cancer dataset shows that the strongest signal (modest number of candidates) can be found by a binary search.

Statistical learning methods as a preprocessing step for survival analysis: evaluation of concept using lung cancer data.

BACKGROUND: Statistical learning (SL) techniques can address non-linear relationships and small datasets but do not provide an output that has an epidemiologic interpretation. METHODS: A small set of clinical variables (CVs) for stage-1 non-small cell lung cancer patients was used to evaluate an approach for using SL methods as a preprocessing step for survival analysis. A stochastic method of training a probabilistic neural network (PNN) was used with differential evolution (DE) optimization. Survival scores were derived stochastically by combining CVs with the PNN. Patients (n = 151) were dichotomized into favorable (n = 92) and unfavorable (n = 59) survival outcome groups. These PNN derived scores were used with logistic regression (LR) modeling to predict favorable survival outcome and were integrated into the survival analysis (i.e. Kaplan-Meier analysis and Cox regression). The hybrid modeling was compared with the respective modeling using raw CVs. The area under the receiver operating characteristic curve (Az) was used to compare model predictive capability. Odds ratios (ORs) and hazard ratios (HRs) were used to compare disease associations with 95% confidence intervals (CIs). RESULTS: The LR model with the best predictive capability gave Az = 0.703. While controlling for gender and tumor grade, the OR = 0.63 (CI: 0.43, 0.91) per standard deviation (SD) increase in age indicates increasing age confers unfavorable outcome. The hybrid LR model gave Az = 0.778 by combining age and tumor grade with the PNN and controlling for gender. The PNN score and age translate inversely with respect to risk. The OR = 0.27 (CI: 0.14, 0.53) per SD increase in PNN score indicates those patients with decreased score confer unfavorable outcome. The tumor grade adjusted hazard for patients above the median age compared with those below the median was HR = 1.78 (CI: 1.06, 3.02), whereas the hazard for those patients below the median PNN score compared to those above the median was HR = 4.0 (CI: 2.13, 7.14). CONCLUSION: We have provided preliminary evidence showing that the SL preprocessing may provide benefits in comparison with accepted approaches. The work will require further evaluation with varying datasets to confirm these findings.

Full field digital mammography and breast density: comparison of calibrated and noncalibrated measurements.

RATIONALE AND OBJECTIVES: Mammographic breast density is an important and widely accepted risk factor for breast cancer. A statement about breast density in the mammographic report is becoming a requirement in many States. However, there is significant inter-observer variation between radiologists in their interpretation of breast density. A properly designed automated system could provide benefits in maintaining consistency and reproducibility. We have developed a new automated and calibrated measure of breast density using full field digital mammography (FFDM). This new measure assesses spatial variation within a mammogram and produced significant associations with breast cancer in a small study. The costs of this automation are delays from advanced image and data analyses before the study can be processed. We evaluated this new calibrated variation measure using a larger dataset than previously. We also explored the possibility of developing an automated measure from unprocessed (raw data) mammograms as an approximation for this calibrated breast density measure. MATERIALS AND METHODS: A case-control study comprised of 160 cases and 160 controls matched by age, screening history, and hormone replacement therapy was used to compare the calibrated variation measure of breast density with three variants of a noncalibrated measure of spatial variation. The operator-assisted percentage of breast density measure (PD) was used as a standard reference for comparison. Odds ratio (OR) quartile analysis was used to compare these measures. Linear regression analysis was applied to assess the calibration's impact on the raw pixel distribution. RESULTS: All breast density measures showed significant breast cancer associations. The calibrated spatial variation measure produced the strongest associations (OR: 1.0 [ref.], 4.6, 4.3, 7.4). The associations for PD were diminished in comparison (OR: 1.0 [ref.], 2.7, 2.9, 5.2). Two additional non-calibrated measures restricted in region size also showed significant associations (OR: 1.0 [ref.], 2.9, 4.4, 5.4), and (OR: 1.0 [ref.], 3.5, 3.1, 4.9). Regression analyses indicated the raw image mean is influenced by the calibration more so than its standard deviation. CONCLUSION: Breast density measures can be automated. The associated calibration produced risk information not retrievable from the raw data representation. Although the calibrated measure produced the stronger association, the non-calibrated measures may offer an alternative to PD and other operator based methods after further evaluation, because they can be implemented automatically with a simple processing algorithm.

A quantitative description of the percentage of breast density measurement using full-field digital mammography.

RATIONALE AND OBJECTIVES: Breast density is a significant breast cancer risk factor that is measured from mammograms. However, uncertainty remains in both understanding its underlying physical properties as it relates to the breast and determining the optimal method for its measurement. A quantitative description of the information captured by the standard operator-assisted percentage of breast density (PD) measure was developed using full-field digital mammography (FFDM) images that were calibrated to adjust for interimage acquisition technique differences. MATERIALS AND METHODS: The information captured by the standard PD measure was quantified by developing a similar measure of breast density (PD(c)) from calibrated mammograms automatically by applying a static threshold to each image. The specific threshold was estimated by first sampling the probability distributions for breast tissue in calibrated mammograms. A percent glandular (PG) measure of breast density was also derived from calibrated mammograms. The PD, PD(c), and PG breast density measures were compared using both linear correlation (R) and quartile odds ratio measures derived from a matched case-control study. RESULTS: The standard PD measure is an estimate of the number of pixel values above a fixed idealized x-ray attenuation fraction. There was significant correlation (P < .0001) between the PD(c)-PD (r = 0.78), PD(c)-PG (r = 0.87), and PD-PG (r = 0.71) measures of breast density. Risk estimates associated with the lowest to highest quartiles for the PD(c) measure (odds ratio [OR]: 1.0 ref., 3.4, 3.6, and 5.6), and the standard PD measure (OR 1.0 ref., 2.9, 4.8, and 5.1) were similar and greater than that of the calibrated PG measure (OR 1.0 ref., 2.0, 2.4, and 2.4). CONCLUSIONS: The information captured by the standard PD measure was quantified as it relates to calibrated mammograms and used to develop an automated method for measuring breast density. These findings represent an initial step for developing an automated measure built on an established calibration platform. A fully developed automated measure may be useful for both research- and clinical-based risk applications.

Calibrated measures for breast density estimation.

RATIONALE AND OBJECTIVES: Breast density is a significant breast cancer risk factor measured from mammograms. Evidence suggests that the spatial variation in mammograms may also be associated with risk. We investigated the variation in calibrated mammograms as a breast cancer risk factor and explored its relationship with other measures of breast density using full field digital mammography (FFDM). MATERIALS AND METHODS: A matched case-control analysis was used to assess a spatial variation breast density measure in calibrated FFDM images, normalized for the image acquisition technique variation. Three measures of breast density were compared between cases and controls: (a) the calibrated average measure, (b) the calibrated variation measure, and (c) the standard percentage of breast density (PD) measure derived from operator-assisted labeling. Linear correlation and statistical relationships between these three breast density measures were also investigated. RESULTS: Risk estimates associated with the lowest to highest quartiles for the calibrated variation measure were greater in magnitude (odds ratios: 1.0 [ref.], 3.5, 6.3, and 11.3) than the corresponding risk estimates for quartiles of the standard PD measure (odds ratios: 1.0 [ref.], 2.3, 5.6, and 6.5) and the calibrated average measure (odds ratios: 1.0 [ref.], 2.4, 2.3, and 4.4). The three breast density measures were highly correlated, showed an inverse relationship with breast area, and related by a mixed distribution relationship. CONCLUSION: The three measures of breast density capture different attributes of the same data field. These preliminary findings indicate the variation measure is a viable automated method for assessing breast density. Insights gained by this work may be used to develop a standard for measuring breast density.

Statistical learning techniques applied to epidemiology: a simulated case-control comparison study with logistic regression.

BACKGROUND: When investigating covariate interactions and group associations with standard regression analyses, the relationship between the response variable and exposure may be difficult to characterize. When the relationship is nonlinear, linear modeling techniques do not capture the nonlinear information content. Statistical learning (SL) techniques with kernels are capable of addressing nonlinear problems without making parametric assumptions. However, these techniques do not produce findings relevant for epidemiologic interpretations. A simulated case-control study was used to contrast the information embedding characteristics and separation boundaries produced by a specific SL technique with logistic regression (LR) modeling representing a parametric approach. The SL technique was comprised of a kernel mapping in combination with a perceptron neural network. Because the LR model has an important epidemiologic interpretation, the SL method was modified to produce the analogous interpretation and generate odds ratios for comparison. RESULTS: The SL approach is capable of generating odds ratios for main effects and risk factor interactions that better capture nonlinear relationships between exposure variables and outcome in comparison with LR. CONCLUSIONS: The integration of SL methods in epidemiology may improve both the understanding and interpretation of complex exposure/disease relationships.

Effective radiation attenuation calibration for breast density: compression thickness influences and correction.

BACKGROUND: Calibrating mammograms to produce a standardized breast density measurement for breast cancer risk analysis requires an accurate spatial measure of the compressed breast thickness. Thickness inaccuracies due to the nominal system readout value and compression paddle orientation induce unacceptable errors in the calibration. METHOD: A thickness correction was developed and evaluated using a fully specified two-component surrogate breast model. A previously developed calibration approach based on effective radiation attenuation coefficient measurements was used in the analysis. Water and oil were used to construct phantoms to replicate the deformable properties of the breast. Phantoms consisting of measured proportions of water and oil were used to estimate calibration errors without correction, evaluate the thickness correction, and investigate the reproducibility of the various calibration representations under compression thickness variations. RESULTS: The average thickness uncertainty due to compression paddle warp was characterized to within 0.5 mm. The relative calibration error was reduced to 7% from 48-68% with the correction. The normalized effective radiation attenuation coefficient (planar) representation was reproducible under intra-sample compression thickness variations compared with calibrated volume measures. CONCLUSION: Incorporating this thickness correction into the rigid breast tissue equivalent calibration method should improve the calibration accuracy of mammograms for risk assessments using the reproducible planar calibration measure.