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612 Background: Observation of heterogeneity in breast pathology has been a consistent theme but one that has had little detailed analysis and/or interpretation. Typically, this research has been limited due to variation in pathology... more
612 Background: Observation of heterogeneity in breast pathology has been a consistent theme but one that has had little detailed analysis and/or interpretation. Typically, this research has been limited due to variation in pathology description by different pathologists. We have utilized a unique breast disease tissue and data repository to infer multiple pathways from breast disease to breast cancer. Methods: Breast pathology diagnoses are drawn from 1029 standardized and highly expanded pathology reports. A single pathologist records the occurrence of any and all pathologies seen in a patient’s breast biopsy. This co-occurrence data is analyzed using a Bayesian network learning algorithm that links data observations in a probabilistic order of events. The resultant Bayesian network is a visualization of how breast disease diagnoses can predict the presence or absence of other diagnoses. For example, a connection between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) visualizes the statement: the presence of DCIS alters the likelihood of the presence of IDC. Results: Separate progression pathways are implicated for DCIS comedo to IDC and DCIS non-comedo to IDC. Multiple breast lesions predict DCIS non-comedo occurrence. One pathway inferred from these predictive lesions is: columnar cell hyperplasia-florid ductal hyperplasia-atypical ductal hyperplasia-DCIS non-comedo-IDC. In contrast, no hyperplasia or atypical lesion can predict DCIS comedo occurrence. That DCIS comedo and DCIS non-comedo have very different progression pathways implies these two pathologies may be two separate diseases. Parallel genomic studies at our institute provide strong evidence that DCIS non-comedo and DCIS comedo are two separate genomic entities. Conclusions: Bayesian network analysis provides a mechanism for the use of heterogeneity in breast disease pathology to predict multiple breast disease progression pathways. Using novel bioinformatic techniques and traditional genomic analysis methods we have gathered compelling evidence that DCIS progression follows two separate pathways. No significant financial relationships to disclose.
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Research Interests: Epidemiology, Cancer, Breast Cancer, Medicine, Comorbidity, and 15 moreHumans, Internal Medicine, African American, Hypertension, Female, Cohort, African Americans, Aged, Adult, Cancer Du Sein, European Continental Ancestry Group, Cancer Registry, Case Control Studies, Breast Neoplasms, and hazard ratio
Breast cancer presents as part of a heterogeneous mix of breast disease pathologies whose biological origins are poorly understood. A systematic and quantitative study of heterogeneity in breast tissue would enable us to characterize the... more
Breast cancer presents as part of a heterogeneous mix of breast disease pathologies whose biological origins are poorly understood. A systematic and quantitative study of heterogeneity in breast tissue would enable us to characterize the disease states present, and use that characterization to guide further research into the complex pathologic associations within breast tissue and between patients. Initially we focus
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At Windber Research Institute we have started research programs that use artificial neural networks (ANNs) in the study of breast cancer in order to identify heterogeneous data predictors of patient disease stages. As an initial effort,... more
At Windber Research Institute we have started research programs that use artificial neural networks (ANNs) in the study of breast cancer in order to identify heterogeneous data predictors of patient disease stages. As an initial effort, we have chosen matrix metalloproteinases (MMPs) as potential biomarker predictors. MMPs have been implicated in the early and late stage development of breast cancer.
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Objective To define pregnancy episodes and estimate gestational aging within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C). Materials and Methods We developed a comprehensive approach, named... more
Objective To define pregnancy episodes and estimate gestational aging within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C). Materials and Methods We developed a comprehensive approach, named Hierarchy and rule-based pregnancy episode Inference integrated with Pregnancy Progression Signatures (HIPPS) and applied it to EHR data in the N3C from 1 January 2018 to 7 April 2022. HIPPS combines: 1) an extension of a previously published pregnancy episode algorithm, 2) a novel algorithm to detect gestational aging-specific signatures of a progressing pregnancy for further episode support, and 3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated three types of pregnancy cohorts based on the level of precision for gestational aging and pregnancy outcomes for comparison of COVID-19 and other characteristics. Results We identified 628,165 pregnant persons with 816,471 pregnancy episodes, o...
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There is a growing emphasis on diversity and its impact on health care. Our research has focused on migrants who are Mandarin speaking Chinese and Puerto Rican. Through a series of focus groups conducted in their native languages we... more
There is a growing emphasis on diversity and its impact on health care. Our research has focused on migrants who are Mandarin speaking Chinese and Puerto Rican. Through a series of focus groups conducted in their native languages we discovered that barriers to service access differ across the two groups. In addition, many of these services are administered by individual states rather than the federal government. The diversity across migrant groups and state policies creates a challenge in using findings to establish national or international standards for best practices with older migrants. How then can we apply lessons about diversity and the impact of programs on a national and international scale? We propose the use of Social Interaction Modeling as a method for understanding patterns of behavior at both national and international levels, while preserving the unique character of each migrant group and the context within which they live.
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Research on older migrants often starts with a set of assumptions- including the importance of language as a barrier to care. A comparative approach allows us to examine these assumptions as they impact access to services for older... more
Research on older migrants often starts with a set of assumptions- including the importance of language as a barrier to care. A comparative approach allows us to examine these assumptions as they impact access to services for older migrants. Our study compared two groups of older migrants – Mandarin speaking Chinese and Spanish speakers from Puerto Rico. Through a series of focus groups we learned that although language can be a barrier to service access, the more important element in reducing disparities for older migrants is the level of trust between older adult and provider. For the older Chinese participants, the presence of a native speaker whom they trust is contrasted with a lack of trusted native Spanish speakers available to Puerto Rican elders, who must often rely on translators from various providers. We will use this example to help explain the differences in service use by these two communities. Part of a symposium sponsored by the International Aging and Migration Int...
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An online issue tracking (QAIT) system was developed to support the QA of questionnaire-based clinical data and tissue banking in the Clinical Breast Care Project (CBCP). The web-based system provides a centralized storage and management... more
An online issue tracking (QAIT) system was developed to support the QA of questionnaire-based clinical data and tissue banking in the Clinical Breast Care Project (CBCP). The web-based system provides a centralized storage and management of QA issues and role-based access to related information and functions via internet. The QAIT system greatly improved the QA process for the CBCP clinical data and tissue banking and can be easily adapted to other applications.
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ABSTRACT
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Array-based comparative genomic hybridization (aCGH) is a recently developed tool for genome-wide determination of DNA copy number alterations. This technology has tremendous potential for disease-gene discovery in cancer and... more
Array-based comparative genomic hybridization (aCGH) is a recently developed tool for genome-wide determination of DNA copy number alterations. This technology has tremendous potential for disease-gene discovery in cancer and developmental disorders as well as numerous other applications. However, widespread utilization of a CGH has been limited by the lack of well characterized, high-resolution clone sets optimized for consistent performance in aCGH assays and specifically designed analytic software. We have assembled a set of ∼4100 publicly available human bacterial artificial chromosome (BAC) clones evenly spaced at ∼1-Mb resolution across the genome, which includes direct coverage of ∼400 known cancer genes. This aCGH-optimized clone set was compiled from five existing sets, experimentally refined, and supplemented for higher resolution and enhancing mapping capabilities. This clone set is associated with a public online resource containing detailed clone mapping data, protocols...
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Breast cancer is the most frequently diagnosed cancer in women, with an estimated 40, 730 breast cancer deaths in the US in 2015. African American (AA) women have a lower breast cancer incidence rate, but a higher breast cancer death... more
Breast cancer is the most frequently diagnosed cancer in women, with an estimated 40, 730 breast cancer deaths in the US in 2015. African American (AA) women have a lower breast cancer incidence rate, but a higher breast cancer death rate, than non-Hispanic White women. Research indicates that breast tumor biology in AA women is different from that in Caucasian women. AA women are more likely to be diagnosed with breast cancer at an earlier age and with more aggressive form of the disease, characterized by higher grade and negative estrogen and progesterone receptor status. Because of the aggressive nature of these tumors and current lack of targeted therapies, identification of novel relevant protein markers is of great importance. The purpose of this study was to validate serum proteins that were previously identified by serum proteomic profiling in 22 serum samples by 2D-DIGE/MS analysis and a subset of samples by shotgun LC/MS technology. Methods and new data: The current study ...
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To date, the actual rate of successful translation has been extremely low although those few successes have been notable and provide for continued and expanding enthusiasm and support. This paper examines whether the fundamental premise... more
To date, the actual rate of successful translation has been extremely low although those few successes have been notable and provide for continued and expanding enthusiasm and support. This paper examines whether the fundamental premise may be flawed. Could the success rate be improved to further enhance quality of life and cost optimization for patients by changing the paradigm to "bedside to bench to bedside", and focusing the research on addressing unmet clinical needs? It examines all aspects of the healthcare ecosystem to understand issues that arise with real world patients and in real world clinical practice and how addressing these should be the focus of translational research.
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The present methods for representing metabolic pathways are limited in their ability to handle complex systems, incorporate new information, and to provide for drawing qualitative conclusions from the structure of pathways. The theory of... more
The present methods for representing metabolic pathways are limited in their ability to handle complex systems, incorporate new information, and to provide for drawing qualitative conclusions from the structure of pathways. The theory of Petri nets is introduced as a tool for computer-implementable representation of pathways. Petri nets have the potential to overcome the present limitations, and through a multitude of properties, enable the preliminary qualitative analysis of pathways.
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4818 Recent advances in serum-based proteomics demonstrate that proteomic pattern analysis could be used as a reliable tool for the diagnosis of many disease states. There is a general interest in the identification of the low molecular... more
4818 Recent advances in serum-based proteomics demonstrate that proteomic pattern analysis could be used as a reliable tool for the diagnosis of many disease states. There is a general interest in the identification of the low molecular weight proteome since these proteins include many that serve as messengers for signaling pathways that govern cell growth and death. Changes in the concentration of these factors in the serum therefore may reflect the pathological condition of a patient’s cells or tissue. However, a major difficulty in analyzing human serum samples still exists due to the presence of high-abundance proteins in the serum (which may constitute greater than 90% of the total serum proteins). The six most highly abundant proteins in human serum are albumin, transferrin, haptoglobin, α1-antitrypsin, immunoglobulins, and α1-acid glycoprotein. High abundance proteins prevent the detection of low-abundance proteins/peptides (
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The pharmaceutical industry is facing tremendous challenges stemming from the low success rates in their research efforts along with the increasing expenses per drug candidate and the urging need for safer and effective therapies to reach... more
The pharmaceutical industry is facing tremendous challenges stemming from the low success rates in their research efforts along with the increasing expenses per drug candidate and the urging need for safer and effective therapies to reach the patients faster. In fact, the average cost per drug candidate exceeds 1 billion Euros and the time to market is still more than 10 years. One of the most important, yet still rather technologically and methodologically poorly supported, steps in clinical research lies in the generation and validation of the hypothesis; i.e. the research question the validity of which a set of clinical trials will aim at proving. Given the intensive searching and knowledge extraction required at this step of the clinical research lifecycle combined with the wealth and constant increase of the available information in literature, the complexity of this process is extremely high and leaves room for a variety of scientific errors and bottlenecks. This paper describ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic management is limited by great uncertainty, for both health systems and citizens. Facing this information gap requires a paradigm shift from traditional approaches to... more
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic management is limited by great uncertainty, for both health systems and citizens. Facing this information gap requires a paradigm shift from traditional approaches to healthcare to the participatory model of improving health. This work describes the design and function of the Doing Risk sElf-assessment and Social health Support for COVID (Dress-COV) system. It aims to establish a lasting link between the user and the tool; thus, enabling modeling of the data to assess individual risk of infection, or developing complications, to improve the individual’s self-empowerment. The system uses bot technology of the Telegram application. The risk assessment includes the collection of user responses and the modeling of data by machine learning models, with increasing appropriateness based on the number of users who join the system. The main results reflect: (a) the individual’s compliance with the tool; (b) the security an...
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There is a growing interest among aging services providers to better understand the pathways through which older adults and their caregivers navigate LTSS. Although there have been attempts at modeling this process they are often... more
There is a growing interest among aging services providers to better understand the pathways through which older adults and their caregivers navigate LTSS. Although there have been attempts at modeling this process they are often dependent on the quality of existing data, which can result in models which are incomplete and study samples that homogenize diverse older adult populations. These models face two challenges – 1) the data may not include information about important elements of the LTSS navigation process, and 2) the actions of ethnic/cultural sub-groups may not be captured. This study uses a conceptual method called Social Interaction Modeling (SIM) to examine how older adults in two limited English-speaking communities (Spanish / Mandarin Chinese) navigate the use of LTSS and to evaluate disparities in service access. The findings will help to build a more comprehensive model which looks at service navigation among all older adults in Philadelphia.
Building on the recent advances in next-generation sequencing, the integration of genomics, proteomics, metabolomics, and other approaches hold tremendous promise for precision medicine. The approval and adoption of these rapidly... more
Building on the recent advances in next-generation sequencing, the integration of genomics, proteomics, metabolomics, and other approaches hold tremendous promise for precision medicine. The approval and adoption of these rapidly advancing technologies and methods presents several regulatory science considerations that need to be addressed. To better understand and address these regulatory science issues, a Clinical and Translational Science Award Working Group convened the Regulatory Science to Advance Precision Medicine Forum. The Forum identified an initial set of regulatory science gaps. The final set of key findings and recommendations provided here address issues related to the lack of standardization of complex tests, preclinical issues, establishing clinical validity and utility, pharmacogenomics considerations, and knowledge gaps.
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The explosive growth of high-throughput experimental methods and resulting data yields both opportunity and challenge for selecting the correct drug to treat both a specific patient and their individual disease. Ideally, it would be... more
The explosive growth of high-throughput experimental methods and resulting data yields both opportunity and challenge for selecting the correct drug to treat both a specific patient and their individual disease. Ideally, it would be useful and efficient if computational approaches could be applied to help achieve optimal drug-patient-disease matching but current efforts have met with limited success. Current approaches have primarily utilized the measureable effect of a specific drug on target tissue or cell lines to identify the potential biological effect of such treatment. While these efforts have met with some level of success, there exists much opportunity for improvement. This specifically follows the observation that, for many diseases in light of actual patient response, there is increasing need for treatment with combinations of drugs rather than single drug therapies. Only a few previous studies have yielded computational approaches for predicting the synergy of drug combi...
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Frailty has been defined in different ways and several diagnostic tools exist, but most of them are not applicable in routine primary care. Nonetheless, general practitioners (GPs) have a natural advantage in identifying frailty, due to... more
Frailty has been defined in different ways and several diagnostic tools exist, but most of them are not applicable in routine primary care. Nonetheless, general practitioners (GPs) have a natural advantage in identifying frailty, due to their continued access to patients, patient-centered approach and training. GPs have also an advantage in conducting population-based evaluation as consequence of their role of gatekeepers of the health care system. This paper aims to identify those socio-demographic and clinical profiles and the relative information sources that, from the GPs' perspective, act as frailty markers, not solely as a diagnosis of state but as the ability to identify a patient's trajectory, over time, through the aging process. This study was performed as a survey within a population aged 75 and over, attending 148 GPs in Italy. A total of 23,996 patients were classified by GPs in distinct frailty status, without the use of a specific evaluation tool, but only ref...
Research Interests: Biochemistry, Data Analysis, Comparative Study, Fourier Analysis, Animals, and 15 moreEnzyme, Cattle, Active site, Fourier transform infrared spectroscopy, Infrared spectra, Protein Conformation, Curve fitting, Infrared Spectrometry, Aqueous Solution, Conformational Change, Biochemistry and cell biology, Molecular Structure, Autolysis, Domestic animal, and Medical biochemistry and metabolomics
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Research Interests: The and CHEMICAL SCIENCES
This study investigates the feasibility of applying Gene Ontology (GO)-derived semantic similarity methods to the biological pathway analysis. The results derived from the analysis of human metabolic and regulatory pathways are consistent... more
This study investigates the feasibility of applying Gene Ontology (GO)-derived semantic similarity methods to the biological pathway analysis. The results derived from the analysis of human metabolic and regulatory pathways are consistent with the network biology. It suggests that the semantic similarity measurement may be used to help the pathway modeling.