Discordant Observations Research Articles

Kappa statistic to measure agreement beyond chance in free-response assessments

BackgroundThe usual kappa statistic requires that all observations be enumerated. However, in free-response assessments, only positive (or abnormal) findings are notified, but negative (or normal) findings are not. This situation occurs frequently in imaging or other diagnostic studies. We propose here a kappa statistic that is suitable for free-response assessments.MethodWe derived the equivalent of Cohen’s kappa statistic for two raters under the assumption that the number of possible findings for any given patient is very large, as well as a formula for sampling variance that is applicable to independent observations (for clustered observations, a bootstrap procedure is proposed). The proposed statistic was applied to a real-life dataset, and compared with the common practice of collapsing observations within a finite number of regions of interest.ResultsThe free-response kappa is computed from the total numbers of discordant (b and c) and concordant positive (d) observations made in all patients, as 2d/(b + c + 2d). In 84 full-body magnetic resonance imaging procedures in children that were evaluated by 2 independent raters, the free-response kappa statistic was 0.820. Aggregation of results within regions of interest resulted in overestimation of agreement beyond chance.ConclusionsThe free-response kappa provides an estimate of agreement beyond chance in situations where only positive findings are reported by raters.

Inverse Sampling for McNemar's Test

Inverse sampling for McNemars test is studied. Sampling is conducted until a pre-specified number of discordant pairs is observed instead of sampling until a pre-specified total number of pairs is observed. The joint likelihood is decomposed into a product of a negative binomial distribution for the number of pairs required to observe r discordant pairs, a binomial distribution for the number of successes in the concordant observations, and a binomial distribution for the number of successes in the discordant observations. Since inference in this problem is based on the discordant observations, inverse sampling controls the type II error when small numbers of discordant observations are observed and the exact binomial test is required. The control results from fixing the sample size for the exact binomial test. Standard sampling instead lets the sample size for the exact binomial test vary and then performs the test conditionally on the observed number of discordant pairs.

Quality control in geochemistry from a comparison of four central tendency and five dispersion estimators and example of a geochemical reference material

Data quality control in geochemistry constitutes a fundamental problem that is still to be solved from the application of statistics and computation. We used refined Monte Carlo simulations of 10,000 replications and 190 independent experiments for sample sizes of 5 to 100. Statistical contaminations of 1 to 4 observations were used to compare 9 statistical parameters (4 central tendency—mean, median, trimean, and Gastwirth mean, and 5 dispersion estimates—standard deviation, median absolute deviation, S n , Q n , and \( {\widehat{\sigma}}_n \)). The presence of discordant observations in the data arrays rendered the outlier-based and robust parameters to disagree with each other. However, when the mean and standard deviation (outlier-based parameters) were estimated from censored data arrays obtained after the identification and separation of outlying observations, they generally provided a better estimate of the population than the robust estimates obtained from the original data arrays. This inference is contrary to the general belief, and therefore, reasons for the better performance of the outlier-based methods as compared to the robust methods are suggested. However, when all parameters were estimated from censored arrays and appropriate precise and accurate correction factors put forth in this work were applied, all of them became fully consistent, i.e., the mean agreed with the median, trimean and Gastwirth mean, and the standard deviation with the median absolute deviation, S n , Q n , and \( {\widehat{\sigma}}_n \). An example of inter-laboratory chemical data for a Hawaiian reference material BHVO-1 included sample sizes from 5 to 100, which showed that small samples of up to 20 provide inconsistent estimates, whereas larger samples of 20–100, especially >40, were more appropriate for estimating statistical parameters through robust or outlier-based methods. Although all statistical estimators provided consistent results, our simulation study shows that it is better to use the censored sample mean and population standard deviation as the best estimates.

Validating the extract, transform, load process used to populate a large clinical research database

BackgroundInformaticians at any institution that are developing clinical research support infrastructure are tasked with populating research databases with data extracted and transformed from their institution’s operational databases, such as electronic health records (EHRs). These data must be properly extracted from these source systems, transformed into a standard data structure, and then loaded into the data warehouse while maintaining the integrity of these data. We validated the correctness of the extract, load, and transform (ETL) process of the extracted data of West Virginia Clinical and Translational Science Institute's Integrated Data Repository, a clinical data warehouse that includes data extracted from two EHR systems. MethodsFour hundred ninety-eight observations were randomly selected from the integrated data repository and compared with the two source EHR systems. ResultsOf the 498 observations, there were 479 concordant and 19 discordant observations. The discordant observations fell into three general categories: a) design decision differences between the IDR and source EHRs, b) timing differences, and c) user interface settings. After resolving apparent discordances, our integrated data repository was found to be 100% accurate relative to its source EHR systems. ConclusionAny institution that uses a clinical data warehouse that is developed based on extraction processes from operational databases, such as EHRs, employs some form of an ETL process. As secondary use of EHR data begins to transform the research landscape, the importance of the basic validation of the extracted EHR data cannot be underestimated and should start with the validation of the extraction process itself.

Discordant Observation of Brain Injury by MRI and Malignant Electroencephalography Patterns in Comatose Survivors of Cardiac Arrest following Therapeutic Hypothermia.

Malignant electroencephalography patterns are considered predictive of poor outcome in comatose survivors of cardiac arrest. We hypothesized that malignant patterns on electroencephalography are associated with evidence of more severe brain injury on MR imaging. Retrospective review of clinical, imaging, and electroencephalography data of 33 adult comatose survivors of cardiac arrest following therapeutic hypothermia was performed. Outcomes measured included discharge destination and survival. Imaging studies were visually scored for severity of brain injury. Mean whole-brain apparent diffusion coefficient and percentage of severely injured brain (ADC < 700 × 10-6 mm2/s) were calculated. Continuous electroencephalographic interpretation was characterized as malignant or nonmalignant. Nonparametric tests were performed to assess the relationship of patient outcome, MR imaging, and electroencephalography patterns. Subjects with anatomic evidence of diffuse brain injury were less likely to have malignant electroencephalography patterns. Subjects with malignant electroencephalography patterns, invariably associated with bad outcomes, were observed to have whole-brain apparent diffusion coefficient measures similar to those in subjects with nonmalignant electroencephalography patterns and good outcome and different from those in subjects with nonmalignant electroencephalography patterns and bad outcomes. Regional hippocampal or basal ganglia injury was associated with a bad outcome regardless of electroencephalography findings. We found discordant evidence of brain injury by MR imaging and electroencephalography, refuting our initial hypothesis. Malignant electroencephalography patterns were generally more frequent in subjects with less severe brain injury by MR imaging. These findings suggest a complementary role of MR imaging and electroencephalography and support the aggressive treatment of malignant electroencephalography patterns in this population.

Programmed Death-Ligand 1 Expression in Muscle-Invasive Bladder Cancer Cystectomy Specimens and Lymph Node Metastasis: A Reliable Treatment Selection Biomarker?

BackgroundThe programmed death-1 (PD-1) pathway negatively regulates T-cell activation and has an important role in regulating antitumor host immunity. Monoclonal antibodies directed against PD-1 or the PD-1 ligand (PD-L1) have shown activity in several tumor types with preliminary data suggesting a relationship between PD-L1 expression and response. The aim of this study was to establish the frequency of PD-L1 expression in muscle-invasive bladder cancer and associated lymph node metastasis using immunohistochemistry and to investigate the feasibility of using PD-L1 expression as a biomarker to select patients for PD–1-directed therapy. Patients and MethodsCases of radical cystectomy for muscle-invasive bladder cancer with no exposure to previous chemotherapy were identified and representative slides from archived paraffin-embedded blocks stained with anti–PD-L1 antibody (5H1 clone) were identified. PD-L1 positivity was defined by a 5% expression threshold. ResultsFifty-two radical cystectomy specimens were reviewed. PD-L1 was overexpressed in the tumor cells of 5/52 (9.6%) of cystectomy specimens in this cohort with 17/52 (32.7%) of cases showing PD-L1 overexpression in tumor-infiltrating immune cells. Discordance was observed between PD-L1 expression in lymph node metastasis and the primary tumor. ConclusionStandard assays for PD-L1 expression have yet to be established. The observation of discordance between PD-L1 expression in metastatic sites and primary tumors suggests that prospective biomarker studies should aim to acquire material immediately before treatment initiation rather than archived tissue from resected specimens that might not reflect the current immune-active microenvironment.

Abstract 2888: Metabolically activated macrophages in obesity associated TNBC

Abstract Triple negative breast cancer (TNBC) accounts for about 20% of all breast cancers. TNBC patients have an extremely poor prognosis due to their high metastatic potential and lack of targeted drug therapies. Emerging epidemiological data suggest that obesity is strongly linked to the incidence and severity of TNBC; obese women have a 35% higher risk of developing TNBC and 46% higher risk of developing distant metastases. Thus, understanding the biological processes that link obesity and TNBC has important clinical applications for prognosis and treatment. Mechanisms by which obesity worsens TNBC prognosis are incompletely understood. One clue to its action is that obesity causes chronic inflammation, and macrophage infiltration into adipose tissue is a key mediator of this inflammation. Recent studies demonstrated that macrophages are enriched in breast adipose tissue of obese humans and mice. Moreover, depletion of macrophages in mice diminished the effects of obesity on TNBC growth and metastasis. Although anti-inflammatory ‘M2-like’ TAMs are key effector cells that promote tumorigenesis, it is well accepted that obesity stimulates macrophages to adopt a pro-inflammatory ‘M1-like’ state. However, M1 macrophages exhibit potent anti-tumor functions. From these discordant observations an important paradox emerges: How can obesity promote breast cancer if it elicits an M1, anti-tumor macrophage phenotype? Using a combination of proteomics, immunology, and cell biology, we recently identified a novel metabolically activated (MMe) macrophage phenotype produced by exposure to high levels of insulin, glucose, and palmitate, conditions characteristic of obese and diabetic patients. Here we show that gene expression patterns in MMe (but not M1) macrophages are strongly associated with pathways involved in breast cancer. Moreover, pre-treating BM1 cells with conditioned media derived from MMe macrophages promotes TNBC cell invasion by 2.3 fold, suggesting that MMe macrophages potentiate metastasis. We further show that breast adipose tissue macrophages isolated from obese women express cell surface markers of MMe (CD36, ABCA1), but not M1 (CD38, CD319, CD274), macrophages. Furthermore, treating naïve macrophages with media conditioned by human mammary adipose tissue from an obese subject (BMI = 37), but not a lean subject (BMI = 19), induced genes diagnostic of the MMe phenotype. Thus, mammary adipose tissue from obese women supports metabolic activation of macrophages. Together, these observations suggest that obesity-induced changes to adipose tissue reprogram macrophages to an MMe phenotype that potentiates TNBC. A comprehensive understanding of signaling mechanisms involved in metabolic activation would enable development of directed therapies towards this specific pro-tumorigenic macrophage phenotype, thereby leaving the immune system of cancer patients intact. Citation Format: Payal Tiwari, Kelly Schoenfelt, Swati Kulkarni, Marsha Rosner, Lev Becker. Metabolically activated macrophages in obesity associated TNBC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2888. doi:10.1158/1538-7445.AM2015-2888

Comorbidity Assessment in Skin Cancer Patients: A Pilot Study Comparing Medical Interview with a Patient-Reported Questionnaire.

Background. Comorbidities are conditions that occur simultaneously but independently of another disorder. Among skin cancer patients, comorbidities are common and may influence management. Objective. We compared comorbidity assessment by traditional medical interview (MI) and by standardized patient-reported questionnaire based on the Adult Comorbidity Evaluation-27 (ACE-27). Methods. Between September 2011 and October 2013, skin cancer patients underwent prospective comorbidity assessment by a Mohs surgeon (MI) and a radiation oncologist (using a standardized patient-reported questionnaire based on the ACE-27, the PRACE-27). Comorbidities were identified and graded according to the ACE-27 and compared for agreement. Results. Forty-four patients were evaluated. MI and PRACE-27 identified comorbidities in 79.5% and 88.6% (p = 0.12) of patients, respectively. Among 27 comorbid ailments, the MI identified 9.9% as being present, while the PRACE-27 identified 12.5%. When there were discordant observations, PRACE-27 was more likely than MI to identify the comorbidity (OR = 5.4, 95% CI = 2.4–14.4, p < 0.001). Overall comorbidity scores were moderate or severe in 43.2% (MI) versus 59.1% (PRACE-27) (p = 0.016). Limitations. Small sample size from a single institution. Conclusion. Comorbidities are common in skin cancer patients, and a standardized questionnaire may better identify and grade them. More accurate comorbidity assessments may help guide skin cancer management.

Identification of Immune and Viral Correlates of Norovirus Protective Immunity through Comparative Study of Intra-Cluster Norovirus Strains

Whether or not primary norovirus infections induce protective immunity has become a controversial issue, potentially confounded by the comparison of data from genetically distinct norovirus strains. Early human volunteer studies performed with a norovirus-positive inoculum initially led to the conclusion that primary infection does not generate long-term, protective immunity. More recently though, the epidemiological pattern of norovirus pandemics has led to the extrapolation that primary norovirus infection induces herd immunity. While these are seemingly discordant observations, they may in fact reflect virus strain-, cluster-, or genogroup-specific differences in protective immunity induction. Here, we report that highly genetically related intra-cluster murine norovirus strains differ dramatically in their ability to induce a protective immune response: Primary MNV-3 infection induced robust and cross-reactive protection, whereas primary MNV-1 infection induced modest homotypic and no heterotypic protection. In addition to this fundamental observation that intra-cluster norovirus strains display remarkable differences in protective immunity induction, we report three additional important observations relevant to norovirus:host interactions. First, antibody and CD4+ T cells are essential to controlling secondary norovirus infections. Second, the viral minor structural protein VP2 regulates the maturation of antigen presenting cells and protective immunity induction in a virus strain-specific manner, pointing to a mechanism by which MNV-1 may prevent the stimulation of memory immune responses. Third, VF1-mediated regulation of cytokine induction also correlates with protective immunity induction. Thus, two highly genetically-related norovirus strains displayed striking differences in induction of protective immune responses, strongly suggesting that the interpretation of norovirus immunity and vaccine studies must consider potential virus strain-specific effects. Moreover, we have identified immune (antibody and CD4+ T cells) and viral (VP2 and possibly VF1) correlates of norovirus protective immunity. These findings have significant implications for our understanding of norovirus immunity during primary infections as well as the development of new norovirus vaccines.

Use of TransFix™ cerebrospinal fluid storage tubes prevents cellular loss and enhances flow cytometric detection of malignant hematological cells after 18 hours of storage

Flow cytometry is a sensitive method for detection of leptomeningeal localizations of hematological malignancies (LHM) in cerebrospinal fluid (CSF). Rapid processing of CSF is needed, as leukocyte numbers appear to decline quickly after lumbar puncture. The cell-stabilizing agent TransFix™ may enhance the detection of LHM in CSF by preventing cellular loss. To study the effects of TransFix on leukocyte numbers and the detection of LHM, we prospectively collected 99 CSF samples from patients with suspected or proven LHM in tubes with (i) TransFix; (ii) serum-containing medium; and (iii) no cell-stabilizing agents (native CSF). Presence of LHM and absolute leukocyte numbers were determined by flow cytometry after 30 minutes and 18 hours of storage. Leukocyte numbers in TransFix-stabilized CSF were higher than in the corresponding native samples at both time points (1.4× and 2.3× respectively, P < 0.0001 on each occasion). After 18 hours of storage, TransFix enhanced the detection of LHM in CSF. In all discordant paired observations (13/99, P = 0.005), the level of suspicion (classified as positive, suspicious, or negative) in CSF with TransFix was higher than in native CSF. We conclude that the use of TransFix-containing CSF storage tubes prevents cellular loss and enhances flow cytometric detection of LHM after 18 hours of storage.

Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity

Bardoxolone methyl and related triterpenoids are well tolerated and efficacious in numerous animal models potentially relevant to patients with Type 2 diabetes and chronic kidney disease. These agents enhance glucose control and regulate lipid accumulation in rodent models of diabetes and obesity, and improve renal function, reduce inflammation, and prevent structural injury in models of renal disease. However, a recent study in Zucker diabetic fatty (ZDF) rats noted poor tolerability with the bardoxolone methyl analog RTA 405 within 1 mo after treatment initiation, although this study was confounded in part by the use of an impure RTA 405 batch. To investigate these discordant observations, the present studies were conducted to further characterize triterpenoids in rodent models of diabetes and obesity. A follow-up study was conducted in ZDF rats with two related triterpenoids (RTA 405 and dh404) for 1.5 mo. Consistent with previous rodent experience, and in contrast to the more recent ZDF report, ZDF rats administered RTA 405 or dh404 exhibited no adverse clinical signs, had laboratory values similar to controls, and exhibited no evidence of adverse liver or kidney histopathology. Additionally, RTA 405 was well tolerated in streptozotocin-induced Type 1 diabetic rats and high-fat-diet-induced obese mice. The present results are consistent with the overall published body of data obtained with triterpenoids and provide further evidence that these molecules are well tolerated without adverse effects on hepatobiliary or renal function in rodent models of diabetes and obesity.

Abstract 5150: What is in control of DNA replication timing.

Abstract The initiation of DNA replication at specific sites in the genome is known to be far from perfect, where known initiation sites may or may not fire in a given single cell during specific cell cycle. At the same time, from larger scale perspective, one finds that the timing of DNA replication is highly orchestrated, where specific regions in the genome are copied at specific, reproducible time points throughout S-phase. In an attempt to reconcile these two somewhat discordant observations, many researchers have assumed that a yet unknown, active regulatory mechanism in the cell is responsible for coordinating replication timing. Here we present a mechanistic explanation for genome-wide replication timing patterns. Our model is purely stochastic, does not contain any active control components and reproduces existing replication timing data with extreme fidelity (correlation &amp;gt; 0.9, about the same as the correlation between technical replicates of the experiment). The main findings of our work are • Existence of reproducible genome-wide replication patterns do not logically necessitate existence of a complex, active control system in the cell • Integrative analysis of recently released ENCODE data identifies semi-local chromatin structure as the main determinant of replication timing • Plasticity of replication timing across different cell types are a direct consequence of changes in the chromatin structure between the different cell differentiation states • Replication timing is a “systems” phenomenon emerging from the collective action of many uncoordinated, stochastic replication initiation sites. Replication timing cannot be understood by investigating individual initiation sites: deleting up to 30% of high probability initiation sites does not significantly change replication timing Citation Format: Yevgeniy Gindin, Paul S. Meltzer, Sven Bilke. What is in control of DNA replication timing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5150. doi:10.1158/1538-7445.AM2013-5150

Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation

RSV lower respiratory tract infections (LRTI) are among the most common diseases necessitating hospital admission in children. In addition to causing acute respiratory failure, RSV infections are associated with sequelae such as secondary bacterial infections and reactive airway disease. One characteristic host response observed in severe RSV-induced LRTI and/or subsequent development of asthma is increased expression of interleukin (IL)-10. However, contradictory results have been reported regarding whether IL-10 inhibits asthmatic responses or intensifies the disease. We aimed to reconcile these discordant observations by elucidating the role of IL-10 in regulating the host response to RSV LRTI. In this study, we used a lung-specific, inducible IL-10 over-expression (OE) transgenic mouse model to address this question. Our results showed that the presence of IL-10 at the time of RSV infection not only attenuated acute inflammatory process (i.e. 24 h post-infection), but also late inflammatory changes [characterized by T helper type 2 (Th2) cytokine and chemokine expression]. While this result appears contradictory to some clinical observations where elevated IL-10 levels are observed in asthmatic patients, we also found that delaying IL-10 OE until the late immune response to RSV infection, additive effects rather than inhibitory effects were observed. Importantly, in non-infected, IL-10 OE mice, IL-10 OE alone induced up-regulation of Th2 cytokine (IL-13 and IL-5) and Th2-related chemokine [monocyte chemoattractant protein 1 (MCP-1), chemokine (C-C motif) ligand 3 (CCL3) and regulated upon activation normal T cell expressed and secreted (RANTES)] expression. We identified a subset of CD11b(+)CD11c(+)CD49b(+)F4/80(-)Gr-1(-) myeloid cells as a prinicipal source of IL-10-induced IL-13 production. Therefore, the augmented pathological responses observed in our 'delayed' IL-10 over-expression model could be attributed to IL-10 OE alone. Taken together, our study indicated dual roles of IL-10 on RSV-induced lung inflammation which appear to depend upon the timing of when elevated IL-10 is expressed in the lung.

Robust Linear Regression Models: Use of a Stable Distribution for the Response Data

In this paper, we study some robustness aspects of linear regression models of the presence of outliers or discordant observations considering the use of stable distributions for the response in place of the usual normality assumption. It is well known that, in general, there is no closed form for the probability density function of stable distributions. However, under a Bayesian approach, the use of a latent or auxiliary random variable gives some simplification to obtain any posterior distribution when related to stable distributions. To show the usefulness of the computational aspects, the methodology is applied to two examples: one is related to a standard linear regression model with an explanatory variable and the other is related to a simulated data set assuming a 23 factorial experiment. Posterior summaries of interest are obtained using MCMC (Markov Chain Monte Carlo) methods and the OpenBugs software.

Mechansim of the Early Stages of the Lamellar/Bicontinuous Cubic Phase Transition

The transition between lamellar and bicontinuous inverted cubic (QII) phases is mediated by catenoidal bilayer channels, which are also the structures that are produced by membrane fusion. The QII phase forms by production of these channels in an array of initially flat bilayers. As the number of channels increase with increasing temperature, they initially form a disordered, metastable array in the lamellar phase, which has been referred to as the “isotropic phase.” The isotropic phase accomplishes the topological change between the lamellar and QII phases. The disordered lattice subsequently transforms into the QII phase by local bending of the bilayers. There are discordant observations concerning the rate of formation and temperature interval of existence for the “isotopic phase.” Here, the expected dimensions of channels are predicted as a function of temperature, as well as the extent of “isotropic phase” formation as a function of temperature and sample water content. The predictions are made using the fourth order curvature energy model previously used to rationalize the stability of the QII phase in phospholipids (Langmuir, 2010, 26:8673). The extent of channel and “isotropic phase” formation is sensitive to the interaction energy of the flat bilayers in the lamellar phase, the lateral dimensions of the lamellar phase bilayers and the sample water volume fraction, as well as the temperature and curvature elastic parameters of the lipid. The theory, as well as the hysteretic nature of the transition process, accounts for the apparent conflict between early observations, made mostly by phosphorus NMR.

Racemose neurocysticercosis and reversible dementia

Sir, The recent publication on racemose neurocysticercosis (NCC) and reversible dementia is very interesting.[1] Sharma et al. reported that “The outcome of dementia patients with NCC seems favorable in most cases; therefore, a high index of suspicion for NCC should be kept, especially in endemic areas.”[1] Indeed, the neurological symptom is not rate in NCC. Indeed, the existing of dementia and cognitive function impairment in NCC is more common in non-calcified active NCC.[2] Nearly, 40% of all non-calcified active NCC can present with dementia. In the real life, dementia might be lately detected and clinical work-up does usually not include looking for NCC. Focusing on the outcome; although, the present report showed favorable outcome.[1] Some previous reports mentioned for discordant observation after complete treatment.[3]

Polymorphisms in genes involved in the metabolism and transport of soy isoflavones affect the urinary metabolite profile in premenopausal women following consumption of a commercial soy supplement as a single bolus dose

Genetic variation in relevant enzymes and transporters may contribute to discordant observations concerning health outcomes of dietary isoflavone consumption, so we examined the association of the UGT1A1*28 promoter polymorphism and of other SNPs with isoflavone metabolites in urine. We genotyped prospectively for polymorphisms in UGT1A1 (UGT1A1*28), LPH (666G>A), CBG (1368T>A), ABCG2 (421C>A), and ABCC2 (1249G>A) to select 100 women (18-50 years) to receive a commercial soy supplement as a single dose and collect all urine over 24 h for analysis by RP-HPLC. We observed large differences in isoflavone recovery (mean 39%, eightfold variation) and metabolites. Glucuronides were the major metabolites (72% of total). UGT1A1*28 was associated only with percentage of glycitein as sulphate (positive; p = 0.046), but excluding five participants with both minor alleles of CBG and ABCG2 uncovered additional associations with percentage of glycitein as glucuronide (negative; p = 0.028), combined isoflavones as sulphate (positive; p = 0.035) and sulphate-to-glucuronide ratio for combined isoflavones (positive; p = 0.036). CBG1368T>A, ABCG2 421C>A, and ABCC2 1249G>A were also associated with differences in isoflavone metabolites in urine. Genetic variation in UGT1A1, CBG, ABCG2, and ABCC2 influences isoflavone metabolism so may affect benefits of dietary consumption.

Diagnostics for repeated measurements in linear mixed effects models

Most currently available methods for detecting discordant subjects and observations in linear mixed effects model fits adapt existing methods for single-level regression data. The most common methods are generalizations of deletion-based approaches, primarily Cook's distance. This article describes the limitations of modifications to Cook's distance and local influence, and suggests a new nondeletion subject-level method, studentized residual sum of squares (TRSS) plots. We also suggest a new observation-level deletion method that detects discordant observations as an application of TRSS plots. The proposed method provides greater information on repeated measurements by utilizing revised residuals and efficiently evaluating the effect of discordant subjects and observations on the estimation of parameters including variance components. We compare the performance of the proposed methods with current methods by using the orthodontic growth data: a longitudinal dataset with 27 subjects each observed four times. TRSS plots successfully identified discordant subjects that were missed by modified Cook's distance methods and the local influence approach. Extensions of TRSS plots are also described.

Abstract PR3: Considering alternate signaling mechanisms models in extrinsic apoptosis using programmatic modeling approaches

Abstract Experiments often result in observations that suggest conflicting biochemical mechanisms in signaling networks. Mathematical modeling of biological systems is a method used to probe such experimental observations and provide a consensus among seemingly discordant observations. However, probing multiple mechanistic hypotheses in biological modeling often involves the instantiation of complex systems of equations, which despite their usefulness, makes model revision, extension, and sharing extremely challenging. To address these modeling barriers, we have developed a modeling framework that brings a process-based approach to biological modeling. In our approach, biological models are written as programs that encode biological functions as needed. Our modeling framework, developed in the Python language, offers access to a large set of existing numerical and programming methods to biological systems modeling. Given our choice of programming language, the resulting models are easier to share, distribute, extend, and revise, adding transparency to the model-creation and execution process. We demonstrate our approach by exploring three competing mechanisms that describe the interactions among the Bcl-2 family of proteins and their contributions to mitochondrial outer membrane permeabilization in extrinsic apoptosis. We used our modeling framework to systematically explore these three proposed mechanisms resulting in the instantiation of sixteen biochemical model topologies for numerical exploration. Our preliminary results, based on simulations calibrated to experimental data, suggest that the so-called indirect mechanism does not accurately reproduce experimental observations. Results from simulations suggest that the so-called embedded model more seems to better align with existing experimental data. Despite these observations, further topology- and numerical-based characterization of the model topology and parameter-space is being carried out to more accurately understand the role of these Bcl-2 proteins in apoptosis. We aim to formulate hypotheses, testable through experiments, about the interaction among these proteins and their role in Bcl-2 cancer biology. This proffered talk is also presented as Poster A9. Citation Format: Carlos F. Lopez, Jeremy L. Muhlich, John J. Bachman, Peter K. Sorger. Considering alternate signaling mechanisms models in extrinsic apoptosis using programmatic modeling approaches [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr PR3.

Treatment of Experimental Data with Discordant Observations: Issues in Empirical Identification of Distribution

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