Bayesian and survival model for tumor relapse status and disease-specific survival, with applications to breast cancer

Breast cancer is the most common non-skin cancer and the second leading cause of cancer-related death in women in the United States. Studies on ipsilateral breast tumor relapse (IBTR) status and disease-specific survival will help guide clinic treatment and predict patient prognosis.^ After breast conservation therapy, patients with breast cancer may experience breast tumor relapse. This relapse is classified into two distinct types: true local recurrence (TR) and new ipsilateral primary tumor (NP). However, the methods used to classify the relapse types are imperfect and are prone to misclassification. In addition, some observed survival data (e.g., time to relapse and time from relapse to death)are strongly correlated with relapse types. The first part of this dissertation presents a Bayesian approach to (1) modeling the potentially misclassified relapse status and the correlated survival information, (2) estimating the sensitivity and specificity of the diagnostic methods, and (3) quantify the covariate effects on event probabilities. A shared frailty was used to account for the within-subject correlation between survival times. The inference was conducted using a Bayesian framework via Markov Chain Monte Carlo simulation implemented in softwareWinBUGS. Simulation was used to validate the Bayesian method and assess its frequentist properties. The new model has two important innovations: (1) it utilizes the additional survival times correlated with the relapse status to improve the parameter estimation, and (2) it provides tools to address the correlation between the two diagnostic methods conditional to the true relapse types.^ Prediction of patients at highest risk for IBTR after local excision of ductal carcinoma in situ (DCIS) remains a clinical concern. The goals of the second part of this dissertation were to evaluate a published nomogram from Memorial Sloan-Kettering Cancer Center, to determine the risk of IBTR in patients with DCIS treated with local excision, and to determine whether there is a subset of patients at low risk of IBTR. Patients who had undergone local excision from 1990 through 2007 at MD Anderson Cancer Center with a final diagnosis of DCIS (n=794) were included in this part. Clinicopathologic factors and the performance of the Memorial Sloan-Kettering Cancer Center nomogram for prediction of IBTR were assessed for 734 patients with complete data. Nomogram for prediction of 5- and 10-year IBTR probabilities were found to demonstrate imperfect calibration and discrimination, with an area under the receiver operating characteristic curve of .63 and a concordance index of .63. In conclusion, predictive models for IBTR in DCIS patients treated with local excision are imperfect. Our current ability to accurately predict recurrence based on clinical parameters is limited.^ The American Joint Committee on Cancer (AJCC) staging of breast cancer is widely used to determine prognosis, yet survival within each AJCC stage shows wide variation and remains unpredictable. For the third part of this dissertation, biologic markers were hypothesized to be responsible for some of this variation, and the addition of biologic markers to current AJCC staging were examined for possibly provide improved prognostication. The initial cohort included patients treated with surgery as first intervention at MDACC from 1997 to 2006. Cox proportional hazards models were used to create prognostic scoring systems. AJCC pathologic staging parameters and biologic tumor markers were investigated to devise the scoring systems. Surveillance Epidemiology and End Results (SEER) data was used as the external cohort to validate the scoring systems. Binary indicators for pathologic stage (PS), estrogen receptor status (E), and tumor grade (G) were summed to create PS+EG scoring systems devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups than the current AJCC staging system. The ability of the PS+EG score to stratify outcomes was confirmed in both internal and external validation cohorts. The current study proposes and validates a new staging system by incorporating tumor grade and ER status into current AJCC staging. We recommend that biologic markers be incorporating into revised versions of the AJCC staging system for patients receiving surgery as the first intervention.^ Chapter 1 focuses on developing a Bayesian method to solve misclassified relapse status and application to breast cancer data. Chapter 2 focuses on evaluation of a breast cancer nomogram for predicting risk of IBTR in patients with DCIS after local excision gives the statement of the problem in the clinical research. Chapter 3 focuses on validation of a novel staging system for disease-specific survival in patients with breast cancer treated with surgery as the first intervention. ^

Guiding functional connectivity estimation by structural connectivity in MEG: an application to discrimination of mild cognitive impaired conditions

Whole brain resting state connectivity is a promising biomarker that might help to obtain an early diagnosis in many neurological diseases, such as dementia. Inferring resting-state connectivity is often based on correlations, which are sensitive to indirect connections, leading to an inaccurate representation of the real backbone of the network. The precision matrix is a better representation for whole brain connectivity, as it considers only direct connections. The network structure can be estimated using the graphical lasso (GL), which achieves sparsity through l1-regularization on the precision matrix. In this paper, we propose a structural connectivity adaptive version of the GL, where weaker anatomical connections are represented as stronger penalties on the corre- sponding functional connections. We applied beamformer source reconstruction to the resting state MEG record- ings of 81 subjects, where 29 were healthy controls, 22 were single-domain amnestic Mild Cognitive Impaired (MCI), and 30 were multiple-domain amnestic MCI. An atlas-based anatomical parcellation of 66 regions was ob- tained for each subject, and time series were assigned to each of the regions. The fiber densities between the re- gions, obtained with deterministic tractography from diffusion-weighted MRI, were used to define the anatomical connectivity. Precision matrices were obtained with the region specific time series in five different frequency bands. We compared our method with the traditional GL and a functional adaptive version of the GL, in terms of log-likelihood and classification accuracies between the three groups. We conclude that introduc- ing an anatomical prior improves the expressivity of the model and, in most cases, leads to a better classification between groups.

Kinetic discrimination in T-cell activation.

We propose a quantitative model for T-cell activation in which the rate of dissociation of ligand from T-cell receptors determines the agonist and antagonist properties of the ligand. The ligands are molecular complexes between antigenic peptides and proteins of the major histocompatibility complex on the surfaces of antigen-presenting cells. Binding of ligand to receptor triggers a series of biochemical reactions in the T cell. If the ligand dissociates after these reactions are complete, the T cell receives a positive activation signal. However, dissociation of ligand after completion of the first reaction but prior to generation of the final products results in partial T-cell activation, which acts to suppress a positive response. Such a negative signal is brought about by T-cell ligands containing the variants of antigenic peptides referred to as T-cell receptor antagonists. Results of recent experiments with altered peptide ligands compare favorably with T-cell responses predicted by this model.

Freedom for individual development : an implementation model for reducing minority and sex role stereotyping /

WI docs. no.: Ed.3/2:9267

Making public employment a model of equal opportunity : a report of the proceedings of Regional Civil Rights Conference II, sponsored by the U.S. Commission on Civil Rights in Boston, Massachusetts, September 22-24, 1974.

Mode of access: Internet.

Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling

The interactions between Eph receptor tyrosine kinases and their ephrin ligands regulate cell migration and axon pathfinding. The EphA receptors are generally thought to become activated by ephrin-A ligands, whereas the EphB receptors interact with ephrin-B ligands. Here we show that two of the most widely studied of these molecules, EphB2 and ephrin-A5, which have never been described to interact with each other, do in fact bind one another with high affinity. Exposure of EphB2-expressing cells to ephrin-A5 leads to receptor clustering, autophosphorylation and initiation of downstream signaling. Ephrin-A5 induces EphB2-mediated growth cone collapse and neurite retraction in a model system. We further show, using X-ray crystallography, that the ephrin-A5-EphB2 complex is a heterodimer and is architecturally distinct from the tetrameric EphB2-ephrin-B2 structure. The structural data reveal the molecular basis for EphB2-ephrin-A5 signaling and provide a framework for understanding the complexities of functional interactions and crosstalk between A- and B-subclass Eph receptors and ephrins.

Contrast discrimination with simultaneous monocular and dichoptic masks

In experiments reported elsewhere at this conference, we have revealed two striking results concerning binocular interactions in a masking paradigm. First, at low mask contrasts, a dichoptic masking grating produces a small facilitatory effect on the detection of a similar test grating. Second, the psychometric slope for dichoptic masking starts high (Weibull ß~4) at detection threshold, becomes low (ß~1.2) in the facilitatory region, and then unusually steep at high mask contrasts (ß~5.5). Neither of these results is consistent with Legge's (1984 Vision Research 24 385 - 394) model of binocular summation, but they are predicted by a two-stage gain control model in which interocular suppression precedes binocular summation. Here, we pose a further challenge for this model by using a 'twin-mask' paradigm (cf Foley, 1994 Journal of the Optical Society of America A 11 1710 - 1719). In 2AFC experiments, observers detected a patch of grating (1 cycle deg-1, 200 ms) presented to one eye in the presence of a pedestal in the same eye and a spatially identical mask in the other eye. The pedestal and mask contrasts varied independently, producing a two-dimensional masking space in which the orthogonal axes (10X10 contrasts) represent conventional dichoptic and monocular masking. The resulting surface (100 thresholds) confirmed and extended the observations above, and fixed the six parameters in the model, which fitted the data well. With no adjustment of parameters, the model described performance in a further experiment where mask and test were presented to both eyes. Moreover, in both model and data, binocular summation was greater than a factor of v2 at detection threshold. We conclude that this two-stage nonlinear model, with interocular suppression, gives a good account of early binocular processes in the perception of contrast. [Supported by EPSRC Grant Reference: GR/S74515/01]

Fixed or variable noise in contrast discrimination? The jury's still out

The ability to distinguish one visual stimulus from another slightly different one depends on the variability of their internal representations. In a recent paper on human visual-contrast discrimination, Kontsevich et al (2002 Vision Research 42 1771 - 1784) re-considered the long-standing question whether the internal noise that limits discrimination is fixed (contrast-invariant) or variable (contrast-dependent). They tested discrimination performance for 3 cycles deg-1 gratings over a wide range of incremental contrast levels at three masking contrasts, and showed that a simple model with an expansive response function and response-dependent noise could fit the data very well. Their conclusion - that noise in visual-discrimination tasks increases markedly with contrast - has profound implications for our understanding and modelling of vision. Here, however, we re-analyse their data, and report that a standard gain-control model with a compressive response function and fixed additive noise can also fit the data remarkably well. Thus these experimental data do not allow us to decide between the two models. The question remains open. [Supported by EPSRC grant GR/S74515/01]

Contrast discrimination and pattern masking: contrast gain control with fixed additive noise

We studied the visual mechanisms that serve to encode spatial contrast at threshold and supra-threshold levels. In a 2AFC contrast-discrimination task, observers had to detect the presence of a vertical 1 cycle deg-1 test grating (of contrast dc) that was superimposed on a similar vertical 1 cycle deg-1 pedestal grating, whereas in pattern masking the test grating was accompanied by a very different masking grating (horizontal 1 cycle deg-1, or oblique 3 cycles deg-1). When expressed as threshold contrast (dc at 75% correct) versus mask contrast (c) our results confirm previous ones in showing a characteristic 'dipper function' for contrast discrimination but a smoothly increasing threshold for pattern masking. However, fresh insight is gained by analysing and modelling performance (p; percent correct) as a joint function of (c, dc) - the performance surface. In contrast discrimination, psychometric functions (p versus logdc) are markedly less steep when c is above threshold, but in pattern masking this reduction of slope did not occur. We explored a standard gain-control model with six free parameters. Three parameters control the contrast response of the detection mechanism and one parameter weights the mask contrast in the cross-channel suppression effect. We assume that signal-detection performance (d') is limited by additive noise of constant variance. Noise level and lapse rate are also fitted parameters of the model. We show that this model accounts very accurately for the whole performance surface in both types of masking, and thus explains the threshold functions and the pattern of variation in psychometric slopes. The cross-channel weight is about 0.20. The model shows that the mechanism response to contrast increment (dc) is linearised by the presence of pedestal contrasts but remains nonlinear in pattern masking.

Size matters, but not for everyone:Individual differences for contrast discrimination

It is very well known that contrast detection thresholds improve with the size of a grating-type stimulus, but it is thought that the benefit of size is abolished for contrast discriminations well above threshold (e.g., Legge, G. E., & Foley, J. M. (1980)]. Here we challenge the generality of this view. We performed contrast detection and contrast discrimination for circular patches of sine wave grating as a function of stimulus size. We confirm that sensitivity improves with approximately the fourth-root of stimulus area at detection threshold (a log-log slope of -0.25) but find individual differences (IDs) for the suprathreshold discrimination task. For several observers, performance was largely unaffected by area, but for others performance first improved (by as much as a log-log slope of -0.5) and then reached a plateau. We replicated these different results several times on the same observers. All of these results were described in the context of a recent gain control model of area summation [Meese, T. S. (2004)], extended to accommodate the multiple stimulus sizes used here. In this model, (i) excitation increased with the fourth-root of stimulus area for all observers, and (ii) IDs in the discrimination data were described by IDs in the relation between suppression and area. This means that empirical summation in the contrast discrimination task can be attributed to growth in suppression with stimulus size that does not keep pace with the growth in excitation. © 2005 ARVO.

A smart sensing platform for the discrimination of human movement

This thesis documents the design, implementation and testing of a smart sensing platform that is able to discriminate between differences or small changes in a persons walking. The distributive tactile sensing method is used to monitor the deflection of the platform surface using just a small number of sensors and, through the use of neural networks, infer the characteristics of the object in contact with the surface. The thesis first describes the development of a mathematical model which uses a novel method to track the position of a moving load as it passes over the smart sensing surface. Experimental methods are then described for using the platform to track the position of swinging pendulum in three dimensions. It is demonstrated that the method can be extended to that of real-time measurement of balance and sway of a person during quiet standing. Current classification methods are then investigated for use in the classification of different gait patterns, in particular to identify individuals by their unique gait pattern. Based on these observations, a novel algorithm is developed that is able to discriminate between abnormal and affected gait. This algorithm, using the distributive tactile sensing method, was found to have greater accuracy than other methods investigated and was designed to be able to cope with any type of gait variation. The system developed in this thesis has applications in the area of medical diagnostics, either as an initial screening tool for detecting walking disorders or to be able to automatically detect changes in gait over time. The system could also be used as a discrete biometric identification method, for example identifying office workers as they pass over the surface.

Bifurcation and stability in a low-dimensional model for multiple-frequency mode-locked lasers

Recent theoretical investigations have demonstrated that the stability of mode-locked solutions of multiple frequency channels depends on the degree of inhomogeneity in gain saturation. In this article, these results are generalized to determine conditions on each of the system parameters necessary for both the stability and the existence of mode-locked pulse solutions for an arbitrary number of frequency channels. In particular, we find that the parameters governing saturable intensity discrimination and gain inhomogeneity in the laser cavity also determine the position of bifurcations of solution types. These bifurcations are completely characterized in terms of these parameters. In addition to influencing the stability of mode-locked solutions, we determine a balance between cubic gain and quintic loss, which is necessary for the existence of solutions as well. Furthermore, we determine the critical degree of inhomogeneous gain broadening required to support pulses in multiple-frequency channels. © 2010 The American Physical Society.

A case study of the Ellison model's use of mentoring as an approach toward inclusive community building

The Ellison Executive Mentoring Inclusive Community Building (ICB) Model is a paradigm for initiating and implementing projects utilizing executives and professionals from a variety of fields and industries, university students, and pre-college students. The model emphasizes adherence to ethical values and promotes inclusiveness in community development. It is a hierarchical model in which actors in each succeeding level of operation serve as mentors to the next. Through a three-step process—content, process, and product—participants must be trained with this mentoring and apprenticeship paradigm in conflict resolution, and they receive sensitivity and diversity training through an interactive and dramatic exposition. ^ The content phase introduces participants to the model's philosophy, ethics, values and methods of operation. The process used to teach and reinforce its precepts is the mentoring and apprenticeship activities and projects in which the participants engage and whose end product demonstrates their knowledge and understanding of the model's concepts. This study sought to ascertain from the participants' perspectives whether the model's mentoring approach is an effective means of fostering inclusiveness, based upon their own experiences in using it. The research utilized a qualitative approach and included data from field observations, individual and group interviews, and written accounts of participants' attitudes. ^ Participants complete ICB projects utilizing The Ellison Model as a method of development and implementation. They generally perceive that the model is a viable tool for dealing with diversity issues whether at work, at school, or at home. The projects are also instructional in that whether participants are mentored or serve as apprentices, they gain useful skills and knowledge about their careers. Since the model is relatively new, there is ample room for research in a variety of areas including organizational studies to determine its effectiveness in combating problems related to various kinds of discrimination. ^

Workplace Discrimination Climate and Team Effectiveness: The Mediating Role of Collective Value Congruence, Team Cohesion, and Collective Affective Commitment

This study explored the relationship between workplace discrimination climate on team effectiveness through three serial mediators: collective value congruence, team cohesion, and collective affective commitment. As more individuals of marginalized groups diversify the workforce and as more organizations move toward team-based work (Cannon-Bowers & Bowers, 2010), it is imperative to understand how employees perceive their organization’s discriminatory climate as well as its effect on teams. An archival dataset consisting of 6,824 respondents was used, resulting in 332 work teams with five or more members in each. The data were collected as part of an employee climate survey administered in 2011 throughout the United States’ Department of Defense. The results revealed that the indirect effect through M1 (collective value congruence) and M2 (team cohesion) best accounted for the relationship between workplace discrimination climate (X) and team effectiveness (Y). Meaning, on average, teams that reported a greater climate for workplace discrimination also reported less collective value congruence with their organization (a1 = -1.07, p < .001). With less shared perceptions of value congruence, there is less team cohesion (d21 = .45, p < .001), and with less team cohesion there is less team effectiveness (b2 = .57, p < .001). In addition, because of theoretical overlap, this study makes the case for studying workplace discrimination under the broader construct of workplace aggression within the I/O psychology literature. Exploratory and confirmatory factor analysis found that workplace discrimination based on five types of marginalized groups: race/ethnicity, gender, religion, age, and disability was best explained by a three-factor model, including: career obstruction based on age and disability bias (CO), verbal aggression based on multiple types of bias (VA), and differential treatment based on racial/ethnic bias (DT). There was initial support to claim that workplace discrimination items covary not only based on type, but also based on form (i.e., nonviolent aggressive behaviors). Therefore, the form of workplace discrimination is just as important as the type when studying climate perceptions and team-level effects. Theoretical and organizational implications are also discussed.

A Case Study of the Ellison Model's Use of Mentoring as an Approach Toward Inclusive Community Building

The Ellison Executive Mentoring Inclusive Community Building (ICB) Model is a paradigm for initiating and implementing projects utilizing executives and professionals from a variety of fields and industries, university students, and pre-college students. The model emphasizes adherence to ethical values and promotes inclusiveness in community development. It is a hierarchical model in which actors in each succeeding level of operation serve as mentors to the next. Through a three-step process--content, process, and product--participants must be trained with this mentoring and apprenticeship paradigm in conflict resolution, and they receive sensitivitiy and diversity training, through an interactive and dramatic exposition. The content phase introduces participants to the model's philosophy, ethics, values and methods of operation. The process used to teach and reinforce its precepts is the mentoring and apprenticeship activities and projects in which the participants engage and whose end product demontrates their knowledge and understanding of the model's concepts. This study sought to ascertain from the participants' perspectives whether the model's mentoring approach is an effective means of fostering inclusiveness, based upon their own experiences in using it. The research utilized a qualitative approach and included data from field observations, individual and group interviews, and written accounts of participants' attitudes. Participants complete ICB projects utilizing the Ellison Model as a method of development and implementation. They generally perceive that the model is a viable tool for dealing with diversity issues whether at work, at school, or at home. The projects are also instructional in that whether participants are mentored or seve as apprentices, they gain useful skills and knowledge about their careers. Since the model is relatively new, there is ample room for research in a variety of areas including organizational studies to dertmine its effectiveness in combating problems related to various kinds of discrimination.