Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction

Background: Metastases are the leading cause of breast cancer-related deaths. The tumor microenvironment impacts cancer progression and metastatic ability. Fibrillar collagen, a major extracellular matrix component, can be studied using the light scattering phenomenon known as second-harmonic generation (SHG). The ratio of forward- to backward-scattered SHG photons (F/B) is sensitive to collagen fiber internal structure and has been shown to be an independent prognostic indicator of metastasis-free survival time (MFS). Here we assess the effects of heterogeneity in the tumor matrix on the possible use of F/B as a prognostic tool. Methods: SHG imaging was performed on sectioned primary tumor excisions from 95 untreated, estrogen receptor-positive, lymph node negative invasive ductal carcinoma patients. We identified two distinct regions whose collagen displayed different average F/B values, indicative of spatial heterogeneity: the cellular tumor bulk and surrounding tumor-stroma interface. To evaluate the impact of heterogeneity on F/B’s prognostic ability, we performed SHG imaging in the tumor bulk and tumor-stroma interface, calculated a 21-gene recurrence score (surrogate for OncotypeDX®, or S-ODX) for each patient and evaluated their combined prognostic ability. Results: We found that F/B measured in tumor-stroma interface, but not tumor bulk, is prognostic of MFS using three methods to select pixels for analysis: an intensity threshold selected by a blinded observer, a histogram-based thresholding method, and an adaptive thresholding method. Using both regression trees and Random Survival Forests for MFS outcome, we obtained data-driven prediction rules that show F/B from tumor-stroma interface, but not tumor bulk, and S-ODX both contribute to predicting MFS in this patient cohort. We also separated patients into low-intermediate (S-ODX < 26) and high risk (S-ODX ≥26) groups. In the low-intermediate risk group, comprised of patients not typically recommended for adjuvant chemotherapy, we find that F/B from the tumor-stroma interface is prognostic of MFS and can identify a patient cohort with poor outcomes. Conclusions: These data demonstrate that intratumoral heterogeneity in F/B values can play an important role in its possible use as a prognostic marker, and that F/B from tumor-stroma interface of prim

Improving on the Positive Part of the UMVUE of a Noncentrality Parameter of a Noncentral Chi-Square Distribution

The purpose of this paper is to give an explicit estimator dominating the positive part of the UMVUE of a noncentrality parameter of a noncentral [chi]2n([mu]/2). Let Y ~ [chi]2n([mu]/2) with degree of freedom n and unknown parameter [mu], LOSS = ([delta] - [mu])2. In his (1974) paper de Waal showed that Y + n is the generalized Bayes estimator of [mu] with respect to a noninformative prior distribution (Comm. Statist.3(1), 73-79). Y - n is the UMVUE of [mu] and dominates Y + n, but is dominated by (Y - n)+. Alam and Saxena (1982, Ann. Statist.10, 1012-1016) showed that (Y - n)+ dominates the MLE of [mu]. Chow (1987, Ann. Statist.15, 800-804) showed that (Y - n)+ is inadmissible. Explicit improvements, however, have not previously been found.

Shrinkage Positive Rule Estimators for Spherically Symmetrical Distributions

Tn the normal case it is well known that, although the James-Stein rule is minimax, it is not admissible and the associated positive rule is one way to improve on it. We extend this result to the class of the spherically symmetric distributions and to a large class of shrinkage rules. Moreover we propose a family of generalized positive rules. We compare our results to those of Berger and Bock (Statistical Decision Theory and Related Topics, II, Academic Press, New York. 1976). In particular our conditions on the shrinkage estimator are weaker.

The effectiveness of an online intervention in preventing excessive gestational weight gain: the e-moms roc randomized controlled trial

Abstract Background Excessive gestational weight gain (GWG) is common and contributes to the development of obesity in women and their offspring. Electronic or e-health interventions have the potential to reach large groups of women and prevent excessive GWG, but their effectiveness has not been demonstrated. The purpose of this study was to evaluate, in a real-world setting, the effectiveness of a self-directed, integrated online and mobile phone behavioral intervention in preventing excessive GWG. Methods This effectiveness trial was a double-blind, three-arm trial with a parallel group design. Two arms received the same e-health intervention during pregnancy with the third arm serving as the placebo control. The intervention was based on a previously efficacious non-digital intervention that was adapted to electronic format. It included three behavior change tools: a weight gain tracker, and separate diet and physical activity goal-setting and self-monitoring tools. Both treatment conditions received access to informational tools, event reminders, and a blogging feature. Healthy pregnant women age 18-35 years with body mass indexes (BMI) ≥18.5 and < 35, at ≤20 weeks gestation, and an e-mail address were eligible. The proportion of women with excessive total GWG, as defined by the Institute of Medicine (IOM), was the primary outcome. 1689 randomized women were analyzed in the intent-to-treat (ITT) analysis. The study was designed to have 87% power to detect a 10 percentage point reduction from a control rate of 55% with a sample of 1641 (p = 0.0167, two-sided). Results In the ITT sample, 48.1% (SD = 2.0%) gained excessively in the intervention group as did 46.2% (SD = 2.4%) in the placebo control group. These proportions were not significantly different (RR 1.09; 95% CI 0.98, 1.20, p = 0.12). The results were not altered in several sensitivity analyses. Conclusion The addition of three behavior change tools to an informational placebo control did not result in a difference in the proportion of women with excessive total GWG compared to the placebo control in this effectiveness trial of an online, self-directed intervention. The similarity of intervention and control treatments and low usage of the behavior change tools in the intervention group are possible explanations. Trial registration NCT01331564, ClinicalTrials.gov