Search

Background: The additive model of inheritance assumes that heterozygotes (Aa) are exactly intermediate in respect to homozygotes (AA and aa). While this model is commonly used in single-locus genetic association studies, significant deviations from additivity are well-documented and contribute to phenotypic variance across many traits and systems. This assumption can introduce type I and type II errors by overestimating or underestimating the effects of variants that deviate from additivity. Alternative genotype encoding strategies have been explored to account for different inheritance patterns, but they often incur significant computational or methodological costs. To address these challenges, we introduce PAGER (Phenotype Adjusted Genotype Encoding and Ranking), an efficient pre-processing method that encodes each genetic variant based on normalized mean phenotypic differences between diallelic genotype classes (AA, Aa, and aa). This approach more accurately reflects each variant's true inheritance model, improving model precision while minimizing the costs associated with alternative encoding strategies., Results: Through extensive benchmarking on SNPs simulated with both binary and continuous phenotypes, we demonstrate that PAGER accurately represents various inheritance patterns (including additive, dominant, recessive, and heterosis), achieves levels of statistical power that meet or exceed other encoding strategies, and attains computation speeds up to 55 times faster than a similar method, EDGE. We also apply PAGER to publicly available real-world data and identify a novel, relevant putative QTL associated with body mass index in rats (Rattus norvegicus) that is not detected with the additive model., Conclusions: Overall, we show that PAGER is an efficient genotype encoding approach that can uncover sources of missing heritability and reveal novel insights in the study of complex traits while incurring minimal costs., (© 2024. The Author(s).)

This work demonstrates the use of cluster analysis in detecting fair and unbiased novel discoveries. Given a sample population of elective spinal fusion patients, we identify two overarching subgroups driven by insurance type. The Medicare group, associated with lower socioeconomic status, exhibited an over-representation of negative risk factors. The findings provide a compelling depiction of the interwoven socioeconomic and racial disparities present within the healthcare system, highlighting their consequential effects on health inequalities. The results are intended to guide design of fair and precise machine learning models based on intentional integration of population stratification.

Autism Spectrum Disorder (ASD) is extremely heterogeneous clinically and genetically. There is a pressing need for a better understanding of the heterogeneity of ASD based on scientifically rigorous approaches centered on systematic evaluation of the clinical and research utility of both phenotype and genotype markers. This paper presents a holistic PheWAS-inspired method to identify meaningful associations between ASD phenotypes and genotypes. We generate two types of phenotype-phenotype (p-p) graphs: a direct graph that utilizes only phenotype data, and an indirect graph that incorporates genotype as well as phenotype data. We introduce a novel methodology for fusing the direct and indirect p-p networks in which the genotype data is incorporated into the phenotype data in varying degrees. The hypothesis is that the heterogeneity of ASD can be distinguished by clustering the p-p graph. The obtained graphs are clustered using network-oriented clustering techniques, and results are evaluated. The most promising clusterings are subsequently analyzed for biological and domain-based relevance. Clusters obtained delineated different aspects of ASD, including differentiating ASD-specific symptoms, cognitive, adaptive, language and communication functions, and behavioral problems. Some of the important genes associated with the clusters have previous known associations to ASD. We found that clusters based on integrated genetic and phenotype data were more effective at identifying relevant genes than clusters constructed from phenotype information alone. These genes included five with suggestive evidence of ASD association and one known to be a strong candidate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Matta, Dobrino, Yeboah, Howard, EL-Manzalawy and Obafemi-Ajayi.)

Concussions, also known as mild traumatic brain injury (mTBI), are a growing health challenge. Approximately four million concussions are diagnosed annually in the United States. Concussion is a heterogeneous disorder in causation, symptoms, and outcome making precision medicine approaches to this disorder important. Persistent disabling symptoms sometimes delay recovery in a difficult to predict subset of mTBI patients. Despite abundant data, clinicians need better tools to assess and predict recovery. Data-driven decision support holds promise for accurate clinical prediction tools for mTBI due to its ability to identify hidden correlations in complex datasets. We apply a Locality-Sensitive Hashing model enhanced by varied statistical methods to cluster blood biomarker level trajectories acquired over multiple time points. Additional features derived from demographics, injury context, neurocognitive assessment, and postural stability assessment are extracted using an autoencoder to augment the model. The data, obtained from FITBIR, consisted of 301 concussed subjects (athletes and cadets). Clustering identified 11 different biomarker trajectories. Two of the trajectories (rising GFAP and rising NF-L) were associated with a greater risk of loss of consciousness or post-traumatic amnesia at onset. The ability to cluster blood biomarker trajectories enhances the possibilities for precision medicine approaches to mTBI.

Today Artificial Intelligence (AI) supports difficult decisions about policy, health, and our personal lives. The AI algorithms we develop and deploy to make sense of information, are informed by data, and based on models that capture and use pertinent details of the population or phenomenon being analyzed. For any application area, more importantly in precision medicine which directly impacts human lives, the data upon which algorithms are run must be procured, cleaned, and organized well to assure reliable and interpretable results, and to assure that they do not perpetrate or amplify human prejudices. This must be done without violating basic assumptions of the algorithms in use. Algorithmic results need to be clearly communicated to stakeholders and domain experts to enable sound conclusions. Our position is that AI holds great promise for supporting precision medicine, but we need to move forward with great care, with consideration for possible ethical implications. We make the case that a no-boundary or convergent approach is essential to support sound and ethical decisions. No-boundary thinking supports problem definition and solving with teams of experts possessing diverse perspectives. When dealing with AI and the data needed to use AI, there is a spectrum of activities that needs the attention of a no-boundary team. This is necessary if we are to draw viable conclusions and develop actions and policies based on the AI, the data, and the scientific foundations of the domain in question., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s) 2021.)

Children with Autism Spectrum Disorder (ASD) exhibit a wide diversity in type, number, and severity of social deficits as well as communicative and cognitive difficulties. It is a challenge to categorize the phenotypes of a particular ASD patient with their unique genetic variants. There is a need for a better understanding of the connections between genotype information and the phenotypes to sort out the heterogeneity of ASD. In this study, single nucleotide polymorphism (SNP) and phenotype data obtained from a simplex ASD sample are combined using a PheWAS-inspired approach to construct a phenotype-phenotype network. The network is clustered, yielding groups of etiologically related phenotypes. These clusters are analyzed to identify relevant genes associated with each set of phenotypes. The results identified multiple discriminant SNPs associated with varied phenotype clusters such as ASD aberrant behavior (self-injury, compulsiveness and hyperactivity), as well as IQ and language skills. Overall, these SNPs were linked to 22 significant genes. An extensive literature search revealed that eight of these are known to have strong evidence of association with ASD. The others have been linked to related disorders such as mental conditions, cognition, and social functioning.Clinical relevance- This study further informs on connections between certain groups of ASD phenotypes and their unique genetic variants. Such insight regarding the heterogeneity of ASD would support clinicians to advance more tailored interventions and improve outcomes for ASD patients.

Background: The use of blood biomarkers after mild traumatic brain injury (mTBI) has been widely studied. We have identified eight unresolved issues related to the use of five commonly investigated blood biomarkers: neurofilament light chain, ubiquitin carboxy-terminal hydrolase-L1, tau, S100B, and glial acidic fibrillary protein. We conducted a focused literature review of unresolved issues in three areas: mode of entry into and exit from the blood, kinetics of blood biomarkers in the blood, and predictive capacity of the blood biomarkers after mTBI., Findings: Although a disruption of the blood brain barrier has been demonstrated in mild and severe traumatic brain injury, biomarkers can enter the blood through pathways that do not require a breach in this barrier. A definitive accounting for the pathways that biomarkers follow from the brain to the blood after mTBI has not been performed. Although preliminary investigations of blood biomarkers kinetics after TBI are available, our current knowledge is incomplete and definitive studies are needed. Optimal sampling times for biomarkers after mTBI have not been established. Kinetic models of blood biomarkers can be informative, but more precise estimates of kinetic parameters are needed. Confounding factors for blood biomarker levels have been identified, but corrections for these factors are not routinely made. Little evidence has emerged to date to suggest that blood biomarker levels correlate with clinical measures of mTBI severity. The significance of elevated biomarker levels thirty or more days following mTBI is uncertain. Blood biomarkers have shown a modest but not definitive ability to distinguish concussed from non-concussed subjects, to detect sub-concussive hits to the head, and to predict recovery from mTBI. Blood biomarkers have performed best at distinguishing CT scan positive from CT scan negative subjects after mTBI., (© 2021. The Author(s).)

Traumatic brain injury (TBI) imposes a significant economic and social burden. The diagnosis and prognosis of mild TBI, also called concussion, is challenging. Concussions are common among contact sport athletes. After a blow to the head, it is often difficult to determine who has had a concussion, who should be withheld from play, if a concussed athlete is ready to return to the field, and which concussed athlete will develop a post-concussion syndrome. Biomarkers can be detected in the cerebrospinal fluid and blood after traumatic brain injury and their levels may have prognostic value. Despite significant investigation, questions remain as to the trajectories of blood biomarker levels over time after mild TBI. Modeling the kinetic behavior of these biomarkers could be informative. We propose a one-compartment kinetic model for S100B, UCH-L1, NF-L, GFAP, and tau biomarker levels after mild TBI based on accepted pharmacokinetic models for oral drug absorption. We approximated model parameters using previously published studies. Since parameter estimates were approximate, we did uncertainty and sensitivity analyses. Using estimated kinetic parameters for each biomarker, we applied the model to an available post-concussion biomarker dataset of UCH-L1, GFAP, tau, and NF-L biomarkers levels. We have demonstrated the feasibility of modeling blood biomarker levels after mild TBI with a one compartment kinetic model. More work is needed to better establish model parameters and to understand the implications of the model for diagnostic use of these blood biomarkers for mild TBI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Azizi, Hier, Allen, Obafemi-Ajayi, Olbricht, Thimgan and Wunsch.)

Feature selection provides a useful method for reducing the size of large data sets while maintaining integrity, thereby improving the accuracy of neural networks and other classifiers. However, running multiple feature selection models and their accompanying classifiers can make interpreting results difficult. To this end, we present a data-driven methodology called Meta-Best that not only returns a single feature set related to a classification target, but also returns an optimal size and ranks the features by importance within the set. This proposed methodology is tested on six distinct targets from the well-known REGARDS dataset: Deceased, Self-Reported Diabetes, Light Alcohol Abuse Risk, Regular NSAID Use, Current Smoker, and Self-Reported Stroke. This methodology is shown to improve the classification rate of neural networks by 0.056 using the ROC Area Under Curve metric compared to a control test with no feature selection.

Clinicians need better tools to assess severity, prognosis, and recovery from mild Traumatic Brain Injury (mTBI), which can cause long term impairment. To enable better mTBI outcome prediction, an initial step is to analyze the trajectory of recovery metrics over time. This study provides an assessment of recovery trajectories of mTBI while incorporating heterogeneity of individual responses. We analyze the trajectories over multiple discrete time points from baseline to 6 months post injury using a combination of neurocognitive and postural stability assessments and serum biomarkers. The data, obtained from FITBIR, consists of concussed subjects and a matched control group, to allow for comparison in prognostic assessment. Outcomes derived from this exploratory analysis will aid future studies in developing a mTBI recovery timeline model.Clinical relevance- This study further informs clinicians as to the recovery trajectory of clinical measures and biomarkers after mTBI to support return to play decisions. GFAP biomarker and measures related to balance, memory, orientation, and concentration were significantly different than controls early after mTBI.

Reliable identification of Inflammatory biomarkers from metagenomics data is a promising direction for developing non-invasive, cost-effective, and rapid clinical tests for early diagnosis of IBD. We present an integrative approach to Network-Based Biomarker Discovery (NBBD) which integrates network analyses methods for prioritizing potential biomarkers and machine learning techniques for assessing the discriminative power of the prioritized biomarkers. Using a large dataset of new-onset pediatric IBD metagenomics biopsy samples, we compare the performance of Random Forest (RF) classifiers trained on features selected using a representative set of traditional feature selection methods against NBBD framework, configured using five different tools for inferring networks from metagenomics data, and nine different methods for prioritizing biomarkers as well as a hybrid approach combining best traditional and NBBD based feature selection. We also examine how the performance of the predictive models for IBD diagnosis varies as a function of the size of the data used for biomarker identification. Our results show that (i) NBBD is competitive with some of the state-of-the-art feature selection methods including Random Forest Feature Importance (RFFI) scores; and (ii) NBBD is especially effective in reliably identifying IBD biomarkers when the number of data samples available for biomarker discovery is small., Competing Interests: The authors have declared that no competing interests exist.

With the growing ubiquity of data in network form, clustering in the context of a network, represented as a graph, has become increasingly important. Clustering is a very useful data exploratory machine learning tool that allows us to make better sense of heterogeneous data by grouping data with similar attributes based on some criteria. This paper investigates the application of a novel graph theoretic clustering method, Node-Based Resilience clustering (NBR-Clust), to address the heterogeneity of Autism Spectrum Disorder (ASD) and identify meaningful subgroups. The hypothesis is that analysis of these subgroups would reveal relevant biomarkers that would provide a better understanding of ASD phenotypic heterogeneity useful for further ASD studies. We address appropriate graph constructions suited for representing the ASD phenotype data. The sample population is drawn from a very large rigorous dataset: Simons Simplex Collection (SSC). Analysis of the results performed using graph quality measures, internal cluster validation measures, and clinical analysis outcome demonstrate the potential usefulness of resilience measure clustering for biomedical datasets. We also conduct feature extraction analysis to characterize relevant biomarkers that delineate the resulting subgroups. The optimal results obtained favored predominantly a 5-cluster configuration., Competing Interests: The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Computer-aided diagnosis provides a medical procedure that assists physicians in interpretation of medical images. This work focuses on computer-aided tongue image analysis specifically, based on Traditional Chinese Medicine (TCM). Tongue diagnosis is an important component of TCM. Computerized tongue diagnosis can aid medical practitioners in capturing quantitative features to improve reliability and consistency of diagnosis. Recently, researchers have started to develop computer-aided tongue analysis algorithms based on new advancement in digital photogrammetry, image analysis, and pattern recognition technologies. In this chapter, we will describe our recent work on tongue image analysis as well as a mobile app that we developed based on this technology.

Heterogeneity in Autism Spectrum Disorder (ASD) is complex including variability in behavioral phenotype as well as clinical, physiologic, and pathologic parameters. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) now diagnoses ASD using a 2-dimensional model based social communication deficits and fixated interests and repetitive behaviors. Sorting out heterogeneity is crucial for study of etiology, diagnosis, treatment and prognosis. In this paper, we present an ensemble model for analyzing ASD phenotypes using several machine learning techniques and a k-dimensional subspace clustering algorithm. Our ensemble also incorporates statistical methods at several stages of analysis. We apply this model to a sample of 208 probands drawn from the Simon Simplex Collection Missouri Site patients. The results provide useful evidence that is helpful in elucidating the phenotype complexity within ASD. Our model can be extended to other disorders that exhibit a diverse range of heterogeneity.

Varied cluster analysis were applied to facial surface measurements from 62 prepubertal boys with essential autism to determine whether facial morphology constitutes viable biomarker for delineation of discrete Autism Spectrum Disorders (ASD) subgroups. Earlier study indicated utility of facial morphology for autism subgrouping (Aldridge et al. in Mol Autism 2(1):15, 2011). Geodesic distances between standardized facial landmarks were measured from three-dimensional stereo-photogrammetric images. Subjects were evaluated for autism-related symptoms, neurologic, cognitive, familial, and phenotypic variants. The most compact cluster is clinically characterized by severe ASD, significant cognitive impairment and language regression. This verifies utility of facially-based ASD subtypes and validates Aldridge et al.'s severe ASD subgroup, notwithstanding different techniques. It suggests that language regression may define a unique ASD subgroup with potential etiologic differences.

ZHENG, Traditional Chinese Medicine syndrome, is an integral and essential part of Traditional Chinese Medicine theory. It defines the theoretical abstraction of the symptom profiles of individual patients and thus, used as a guideline in disease classification in Chinese medicine. For example, patients suffering from gastritis may be classified as Cold or Hot ZHENG, whereas patients with different diseases may be classified under the same ZHENG. Tongue appearance is a valuable diagnostic tool for determining ZHENG in patients. In this paper, we explore new modalities for the clinical characterization of ZHENG using various supervised machine learning algorithms. We propose a novel-color-space-based feature set, which can be extracted from tongue images of clinical patients to build an automated ZHENG classification system. Given that Chinese medical practitioners usually observe the tongue color and coating to determine a ZHENG type and to diagnose different stomach disorders including gastritis, we propose using machine-learning techniques to establish the relationship between the tongue image features and ZHENG by learning through examples. The experimental results obtained over a set of 263 gastritis patients, most of whom suffering Cold Zheng or Hot ZHENG, and a control group of 48 healthy volunteers demonstrate an excellent performance of our proposed system.