The Application of Knowledge Engineering via the Use of a Biomimetic Digital Twin Ecosystem, Phenotype-Driven Variant Analysis, and Exome Sequencing to Understand the Molecular Mechanisms of Disease.

Applied artificial intelligence, particularly large language models, in biomedical research is accelerating, but effective discovery and validation requires a toolset without limitations or bias. On January 30, 2023, the National Academies of Sciences, Engineering, and Medicine (NAS) appointed an ad hoc committee to identify the needs and opportunities to advance the mathematical, statistical, and computational foundations of digital twins in applications across science, medicine, engineering, and society. On December 15, 2023, the NAS released a 164-page report, "Foundational Research Gaps and Future Directions for Digital Twins." This report described the importance of using digital twins in biomedical research. The current study was designed to develop an innovative method that incorporated phenotype-ranking algorithms with knowledge engineering via a biomimetic digital twin ecosystem. This ecosystem applied real-world reasoning principles to nonnormalized, raw data to identify hidden or "dark" data. Clinical exome sequencing study on patients with endometriosis indicated four variants of unknown clinical significance potentially associated with endometriosis-related disorders in nearly all patients analyzed. One variant of unknown clinical significance was identified in all patient samples and could be a biomarker for diagnostics. To the best of our knowledge, this is the first study to incorporate the recommendations of the NAS to biomedical research. This method can be used to understand the mechanisms of any disease, for virtual clinical trials, and to identify effective new therapies.

Public perceptions of psychiatric, justice-involved, and elderly populations during the COVID-19 pandemic.

The novel coronavirus disease (COVID-19) has had a significant global impact, with all countries facing the challenge of mitigating its spread. An unprecedented shortage of medical resources has raised concerns regarding allocation and prioritization of supplies, which may exacerbate social discrepancies for already vulnerable populations. As public opinion can impact healthcare policies, we aimed to characterize perceptions of psychiatric, forensic psychiatry, correctional, and elderly populations regarding COVID-19-related issues. This web-based study recruited participants (n = 583) from the general population in North America. The survey included perceptions of the pandemic, hypothetical scenarios on resource prioritization, and Likert scale questions. The majority of participants were cisgender female (72.7%), aged 31-74 years (80.0%), married (48.0%), retired (52.7%), resided in Canada (73.9%), had a college/university degree (50.9%) and had never worked in healthcare (66.21%). Most respondents reported not having a criminal history (95.88%), or a psychiatric disorder (78.73%). Perceptions of vulnerable populations were significantly different for resource allocation and prioritization (e.g., ventilator and vaccine resources, all p < 0.001). Healthcare workers and the elderly were commonly ranked the highest priority for resources, while forensic psychiatry and correctional populations were given the lowest priority. A high rate of disagreement was found for the more stigmatizing questions in the survey (all p < 0.0001). Our results suggest that perception from members of the general public in North America is aligned with current practices for resource allocation. However, individuals that already face social and health disparities may face additional opposition in decision-making for COVID-19 resources.

Genetic Polymorphisms in IL-10 Promoter Are Associated With Smoking and Prostate Cancer Risk in African Americans.

BACKGROUND/AIM: Even though prostate cancer (PCa) has good prognosis, there is a discrepancy in the risk among ethnic groups, with high morbidity in African American men. Single nucleotide polymorphisms (SNPs) in interleukin 10 (IL-10) have been associated with inflammation and cancer risk. We investigated the association of five SNPs in the IL-10 promoter with clinical features such as Gleason score and smoking. MATERIALS AND METHODS: A total of 413 DNA samples were obtained from a nested case-control study of African American males who were genotyped for 5 SNPs utilizing pyrosequencing. Multiple and binary logistic regression models were applied to analyze the clinical and genotypic data. RESULTS: rs12122923 and rs1800871 were associated with PCa risk. Smoking was also found to increase the risk of PCa by 1.6-fold. rs1800893 was found to be associated with lower grades for prostate cancer. CONCLUSION: IL-10 promoter polymorphisms might be a risk factor for PCa development in smoking subjects and PCa progression.

Admixture Mapping Links RACGAP1 Regulation to Prostate Cancer in African Americans.

BACKGROUND/AIM: Prostate cancer is the most common malignancy in US males. African American men have higher incidence and mortality rates than European Americans. Five single nucleotide polymorphisms are associated with PCa. We hypothesized haplotypes inferred from these SNPs are also associated with PCa. PATIENTS AND METHODS: We genotyped SNPs in a case-control admixture mapping study. SNP haplotypes inferred for 157 PCa cases and 150 controls were used in the regression analysis. RESULTS: We found an association between "GTCCC", "ATTCT", and "ACCCC" haplotypes and PCa after ancestry adjustment (OR=3.62, 95%CI=1.42-9.21, p=0.0070; OR=7.89, 95%CI=2.36-26.31, p=0.0008; OR=4.34, 95%CI=1.75-10.78, p=0.0016). The rs615382 variant disrupts the recombination signal binding protein with immunoglobulin kappa J binding site in Rac GTPase activating protein 1 (RACGAP1). CONCLUSION: Disruption of notch 1 mediated-repression of RACGAP1 may contribute to PCa in African Americans.

Next Generation Sequencing Reveals High Prevalence of BRCA1 and BRCA2 Variants of Unknown Significance in Early-Onset Breast Cancer in African American Women.

BACKGROUND: Variants of unknown significance (VUSs) have been identified in BRCA1 and BRCA2 and account for the majority of all identified sequence alterations. Notably, VUSs occur disproportionately in people of African descent hampering breast cancer (BCa) management and prevention efforts in the population. Our study sought to identify and characterize mutations associated with increased risk of BCa at young age. METHODS: In our study, the spectrum of mutations in BRCA1 and BRCA2 was enumerated in a cohort of 31 African American women of early age at onset breast cancer, with a family history of breast or cancer in general and/or with triple negative breast cancer. To improve the characterization of the BRCA1 and BRCA2 variants, bioinformatics tools were utilized to predict the potential function of each of the variants. RESULTS: Using next generation sequencing methods and in silico analysis of variants, a total of 197 BRCA1 and 266 BRCA2 variants comprising 77 unique variants were identified in 31 patients. Of the 77 unique variants, one (1.3%) was a pathogenic frameshift mutation (rs80359304; BRCA2 Met591Ile), 13 (16.9%) were possibly pathogenic, 34 (44.2%) were benign, and 29 (37.7%) were VUSs. Genetic epidemiological approaches were used to determine the association with variant, haplotype, and phenotypes, such as age at diagnosis, family history of cancer and family history of breast cancer. There were 5 BRCA1 SNPs associated with age at diagnosis; rs1799966 (P=.045; Log Additive model), rs16942 (P=.033; Log Additive model), rs1799949 (P=.058; Log Additive model), rs373413425 (P=.040 and .023; Dominant and Log Additive models, respectively) and rs3765640 (P=.033 Log Additive model). Additionally, a haplotype composed of all 5 SNPs was found to be significantly associated with younger age at diagnosis using linear regression modeling (P=.023). Specifically, the haplotype containing all the variant alleles was associated with older age at diagnosis (OR= 5.03 95% CI=.91-9.14). CONCLUSIONS: Knowing a patient's BRCA mutation status is important for prevention and treatment decision-making. Improving the characterization of mutations will lead to better management, treatment, and BCa prevention efforts in African Americans who are disproportionately affected with aggressive BCa and may inform future precision medicine genomic-based clinical studies.

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

INTRODUCTION: Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. METHODS: We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. RESULTS: At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. CONCLUSION: Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

Family history of cancer associated with breast tumor clinicopathological features.

Hereditary breast cancers have unique clinicopathological characteristics. Therefore, the objective of this study was to establish the relationship between self-reported family history of cancer and clinicopathological features in breast cancer patients from Washington, DC. Data on incident breast cancer cases from 2000 to 2010 were obtained from the Washington, DC Cancer Registry. Variables such as estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptor status, as well as stage and grade, were analyzed in those that self-reported with (n = 1,734) and without a family history of cancer (n = 1,712). The breast cancer molecular subtypes were compared when ER, PR, and HER2 statuses were available. Furthermore, tumor characteristics were compared by race/ethnicity. Regression and chi-square analyses were performed. A report of family history was associated with age (OR = 1.27 95 % CI: 1.09-1.48; p < 0.0001), high grade tumors (OR = 1.29 95 % CI: 1.05-1.58; p = 0.02), and having ER and PR negative breast cancer (OR = 1.26 95 % CI: 1.02-1.57; p = 0.029). When tumor characteristics were compared by race/ethnicity, those that self-reported as African American with a family history had a higher frequency of ER negative tumors (OR = 1.51 95 % CI: 1.09-2.08; p = 0.008), PR negative tumors (OR = 1.46 95 % CI: 1.09-1.94; p = 0.028), grade 3 tumors (OR = 1.42 95 % CI: 1.05-1.93; p < 0.0001), and ER/PR negative tumors (OR = 1.5 95 % CI: 1.088-2.064; p = 0.01). These results suggest that a positive family history of cancer in African Americans should increase suspicions of hereditary cancer. Therefore, behavioral risk reduction activities, such as collecting a family history, may reduce late stage diagnosis and cancer mortality.