arXiv subjects

Danielle Braun

Publications and source records attributed to Danielle Braun.

27 records · Page 2Linked to original sources

arXiv2021

Matching on Generalized Propensity Scores with Continuous Exposures

In the context of a binary treatment, matching is a well-established approach in causal inference. However, in the context of a continuous treatment or exposure, matching is still underdeveloped. We propose an innovative matching approach to estimate an average causal exposure-response function under the setting of continuous exposures that relies on the generalized propensity score (GPS). Our approach maintains the following attractive features of matching: a) clear separation between the design and the analysis; b) robustness to model misspecification or to the presence of extreme values of the estimated GPS; c) straightforward assessment of covariate balance. We first introduce an assumption of identifiability, called local weak unconfoundedness. Under this assumption and mild smoothness conditions, we provide theoretical guarantees that our proposed matching estimator attains point-wise consistency and asymptotic normality. In simulations, our proposed matching approach outperforms existing methods under settings of model misspecification or the presence of extreme values of the estimated GPS. We apply our proposed method to estimate the average causal exposure-response function between long-term PM$_{2.5}$ exposure and all-cause mortality among 68.5 million Medicare enrollees, 2000-2016. We found strong evidence of a harmful effect of long-term PM$_{2.5}$ exposure on mortality. Code for the proposed matching approach is provided in the CausalGPS R package, which is available on CRAN and provides a computationally efficient implementation.

stat.ME↗

arXiv2021

Prediction of Hereditary Cancers Using Neural Networks

Family history is a major risk factor for many types of cancer. Mendelian risk prediction models translate family histories into cancer risk predictions based on knowledge of cancer susceptibility genes. These models are widely used in clinical practice to help identify high-risk individuals. Mendelian models leverage the entire family history, but they rely on many assumptions about cancer susceptibility genes that are either unrealistic or challenging to validate due to low mutation prevalence. Training more flexible models, such as neural networks, on large databases of pedigrees can potentially lead to accuracy gains. In this paper, we develop a framework to apply neural networks to family history data and investigate their ability to learn inherited susceptibility to cancer. While there is an extensive literature on neural networks and their state-of-the-art performance in many tasks, there is little work applying them to family history data. We propose adaptations of fully-connected neural networks and convolutional neural networks to pedigrees. In data simulated under Mendelian inheritance, we demonstrate that our proposed neural network models are able to achieve nearly optimal prediction performance. Moreover, when the observed family history includes misreported cancer diagnoses, neural networks are able to outperform the Mendelian BRCAPRO model embedding the correct inheritance laws. Using a large dataset of over 200,000 family histories, the Risk Service cohort, we train prediction models for future risk of breast cancer. We validate the models using data from the Cancer Genetics Network.

stat.ML↗

arXiv2021

Extending Models Via Gradient Boosting: An Application to Mendelian Models

Improving existing widely-adopted prediction models is often a more efficient and robust way towards progress than training new models from scratch. Existing models may (a) incorporate complex mechanistic knowledge, (b) leverage proprietary information and, (c) have surmounted barriers to adoption. Compared to model training, model improvement and modification receive little attention. In this paper we propose a general approach to model improvement: we combine gradient boosting with any previously developed model to improve model performance while retaining important existing characteristics. To exemplify, we consider the context of Mendelian models, which estimate the probability of carrying genetic mutations that confer susceptibility to disease by using family pedigrees and health histories of family members. Via simulations we show that integration of gradient boosting with an existing Mendelian model can produce an improved model that outperforms both that model and the model built using gradient boosting alone. We illustrate the approach on genetic testing data from the USC-Stanford Cancer Genetics Hereditary Cancer Panel (HCP) study.

stat.AP↗

arXiv2020

PanelPRO: A R package for multi-syndrome, multi-gene risk modeling for individuals with a family history of cancer

Identifying individuals who are at high risk of cancer due to inherited germline mutations is critical for effective implementation of personalized prevention strategies. Most existing models to identify these individuals focus on specific syndromes by including family and personal history for a small number of cancers. Recent evidence from multi-gene panel testing has shown that many syndromes once thought to be distinct are overlapping, motivating the development of models that incorporate family history information on several cancers and predict mutations for more comprehensive panels of genes. Once such class of models are Mendelian risk prediction models, which use family history information and Mendelian laws of inheritance to estimate the probability of carrying genetic mutations, as well as future risk of developing associated cancers. To flexibly model the complexity of many cancer-mutation associations, we present a new software tool called PanelPRO, a R package that extends the previously developed BayesMendel R package to user-selected lists of susceptibility genes and associated cancers. The model identifies individuals at an increased risk of carrying cancer susceptibility gene mutations and predicts future risk of developing hereditary cancers associated with those genes. Additional functionalities adjust for prophylactic interventions, known genetic testing results, and risk modifiers such as race and ancestry. The package comes with a customizable database with default parameter values estimated from published studies. The PanelPRO package is open-source and provides a fast and flexible back-end for multi-gene, multi-cancer risk modeling with pedigree data. The software enables the identification of high-risk individuals, which will have an impact on personalized prevention strategies for cancer and individualized decision making about genetic testing.

stat.AP↗

arXiv2020

Combining Breast Cancer Risk Prediction Models

Accurate risk stratification is key to reducing cancer morbidity through targeted screening and preventative interventions. Numerous breast cancer risk prediction models have been developed, but they often give predictions with conflicting clinical implications. Integrating information from different models may improve the accuracy of risk predictions, which would be valuable for both clinicians and patients. BRCAPRO and BCRAT are two widely used models based on largely complementary sets of risk factors. BRCAPRO is a Bayesian model that uses detailed family history information to estimate the probability of carrying a BRCA1/2 mutation, as well as future risk of breast and ovarian cancer, based on mutation prevalence and penetrance (age-specific probability of developing cancer given genotype). BCRAT uses a relative hazard model based on first-degree family history and non-genetic risk factors. We consider two approaches for combining BRCAPRO and BCRAT: 1) modifying the penetrance functions in BRCAPRO using relative hazard estimates from BCRAT, and 2) training an ensemble model that takes as input BRCAPRO and BCRAT predictions. We show that the combination models achieve performance gains over BRCAPRO and BCRAT in simulations and data from the Cancer Genetics Network.

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arXiv2019

Ask2Me VarHarmonizer: A Python-Based Tool to Harmonize Variants from Cancer Genetic Testing Reports and Map them to the ClinVar Database

PURPOSE: The popularity of germline genetic panel testing has led to a vast accumulation of variant-level data. Variant names are not always consistent across laboratories and not easily mappable to public variant databases such as ClinVar. A tool that can automate the process of variants harmonization and mapping is needed to help clinicians ensure their variant interpretations are accurate. METHODS: We present a Python-based tool, Ask2Me VarHarmonizer, that incorporates data cleaning, name harmonization, and a four-attempt mapping to ClinVar procedure. We applied this tool to map variants from a pilot dataset collected from 11 clinical practices. Mapping results were evaluated with and without the transcript information. RESULTS: Using Ask2Me VarHarmonizer, 4728 out of 6027 variant entries (78%) were successfully mapped to ClinVar, corresponding to 3699 mappable unique variants. With the addition of 1099 unique unmappable variants, a total of 4798 unique variants were eventually identified. 427 (9%) of these had multiple names, of which 343 (7%) had multiple names within-practice. 99% mapping consistency was observed with and without transcript information. CONCLUSION: Ask2Me VarHarmonizer aggregates and structures variant data, harmonizes names, and maps variants to ClinVar. Performing harmonization removes the ambiguity and redundancy of variants from different sources.

q-bio.QM↗

arXiv2019

Using Machine Learning and Natural Language Processing to Review and Classify the Medical Literature on Cancer Susceptibility Genes

PURPOSE: The medical literature relevant to germline genetics is growing exponentially. Clinicians need tools monitoring and prioritizing the literature to understand the clinical implications of the pathogenic genetic variants. We developed and evaluated two machine learning models to classify abstracts as relevant to the penetrance (risk of cancer for germline mutation carriers) or prevalence of germline genetic mutations. METHODS: We conducted literature searches in PubMed and retrieved paper titles and abstracts to create an annotated dataset for training and evaluating the two machine learning classification models. Our first model is a support vector machine (SVM) which learns a linear decision rule based on the bag-of-ngrams representation of each title and abstract. Our second model is a convolutional neural network (CNN) which learns a complex nonlinear decision rule based on the raw title and abstract. We evaluated the performance of the two models on the classification of papers as relevant to penetrance or prevalence. RESULTS: For penetrance classification, we annotated 3740 paper titles and abstracts and used 60% for training the model, 20% for tuning the model, and 20% for evaluating the model. The SVM model achieves 89.53% accuracy (percentage of papers that were correctly classified) while the CNN model achieves 88.95 % accuracy. For prevalence classification, we annotated 3753 paper titles and abstracts. The SVM model achieves 89.14% accuracy while the CNN model achieves 89.13 % accuracy. CONCLUSION: Our models achieve high accuracy in classifying abstracts as relevant to penetrance or prevalence. By facilitating literature review, this tool could help clinicians and researchers keep abreast of the burgeoning knowledge of gene-cancer associations and keep the knowledge bases for clinical decision support tools up to date.

cs.IR↗

arXiv2018

airpred: A Flexible R Package Implementing Methods for Predicting Air Pollution

Fine particulate matter (PM$_{2.5}$) is one of the criteria air pollutants regulated by the Environmental Protection Agency in the United States. There is strong evidence that ambient exposure to (PM$_{2.5}$) increases risk of mortality and hospitalization. Large scale epidemiological studies on the health effects of PM$_{2.5}$ provide the necessary evidence base for lowering the safety standards and inform regulatory policy. However, ambient monitors of PM$_{2.5}$ (as well as monitors for other pollutants) are sparsely located across the U.S., and therefore studies based only on the levels of PM$_{2.5}$ measured from the monitors would inevitably exclude large amounts of the population. One approach to resolving this issue has been developing models to predict local PM$_{2.5}$, NO$_2$, and ozone based on satellite, meteorological, and land use data. This process typically relies developing a prediction model that relies on large amounts of input data and is highly computationally intensive to predict levels of air pollution in unmonitored areas. We have developed a flexible R package that allows for environmental health researchers to design and train spatio-temporal models capable of predicting multiple pollutants, including PM$_{2.5}$. We utilize H2O, an open source big data platform, to achieve both performance and scalability when used in conjunction with cloud or cluster computing systems.

stat.ML↗

arXiv2018

Causal inference in the context of an error prone exposure: air pollution and mortality

We propose a new approach for estimating causal effects when the exposure is measured with error and confounding adjustment is performed via a generalized propensity score (GPS). Using validation data, we propose a regression calibration (RC)-based adjustment for a continuous error-prone exposure combined with GPS to adjust for confounding (RC-GPS). The outcome analysis is conducted after transforming the corrected continuous exposure into a categorical exposure. We consider confounding adjustment in the context of GPS subclassification, inverse probability treatment weighting (IPTW) and matching. In simulations with varying degrees of exposure error and confounding bias, RC-GPS eliminates bias from exposure error and confounding compared to standard approaches that rely on the error-prone exposure. We applied RC-GPS to a rich data platform to estimate the causal effect of long-term exposure to fine particles ($PM_{2.5}$) on mortality in New England for the period from 2000 to 2012. The main study consists of $2,202$ zip codes covered by $217,660$ 1km $\times$ 1km grid cells with yearly mortality rates, yearly $PM_{2.5}$ averages estimated from a spatio-temporal model (error-prone exposure) and several potential confounders. The internal validation study includes a subset of 83 1km $\times$ 1km grid cells within 75 zip codes from the main study with error-free yearly $PM_{2.5}$ exposures obtained from monitor stations. Under assumptions of non-interference and weak unconfoundedness, using matching we found that exposure to moderate levels of $PM_{2.5}$ ($8 <$ $PM_{2.5}$ $\leq 10\ {\rm μg/m^3}$) causes a $2.8\%$ ($95\%$ CI: $0.6\%, 3.6\%$) increase in all-cause mortality compared to low exposure ($PM_{2.5}$ $\leq 8\ {\rm μg/m^3}$).

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