Browsing by Subject "Predictive markers"
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Item A proteogenomic view of Parkinson's disease causality and heterogeneity(Springer Nature, 2023-02-11) Kaiser, Sergio; Zhang, Luqing; Mollenhauer, Brit; Jacob, Jaison; Longerich, Simonne; Del-Aguila, Jorge; Marcus, Jacob; Raghavan, Neha; Stone, David; Fagboyegun, Olumide; Galasko, Douglas; Dakna, Mohammed; Bilican, Bilada; Dovlatyan, Mary; Kostikova, Anna; Li, Jingyao; Peterson, Brant; Rotte, Michael; Sanz, Vinicius; Foroud, Tatiana; Hutten, Samantha J.; Frasier, Mark; Iwaki, Hirotaka; Singleton, Andrew; Marek, Ken; Crawford, Karen; Elwood, Fiona; Messa, Mirko; Serrano-Fernandez, Pablo; Medical and Molecular Genetics, School of MedicineThe pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into “endotypes”. The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.Item An interpretable Alzheimer's disease oligogenic risk score informed by neuroimaging biomarkers improves risk prediction and stratification(Frontiers Media, 2023-10-26) Suh, Erica H.; Lee, Garam; Jung, Sang-Hyuk; Wen, Zixuan; Bao, Jingxuan; Nho, Kwangsik; Huang, Heng; Davatzikos, Christos; Saykin, Andrew J.; Thompson, Paul M.; Shen, Li; Kim, Dokyoon; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineIntroduction: Stratification of Alzheimer's disease (AD) patients into risk subgroups using Polygenic Risk Scores (PRS) presents novel opportunities for the development of clinical trials and disease-modifying therapies. However, the heterogeneous nature of AD continues to pose significant challenges for the clinical broadscale use of PRS. PRS remains unfit in demonstrating sufficient accuracy in risk prediction, particularly for individuals with mild cognitive impairment (MCI), and in allowing feasible interpretation of specific genes or SNPs contributing to disease risk. We propose adORS, a novel oligogenic risk score for AD, to better predict risk of disease by using an optimized list of relevant genetic risk factors. Methods: Using whole genome sequencing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n = 1,545), we selected 20 genes that exhibited the strongest correlations with FDG-PET and AV45-PET, recognized neuroimaging biomarkers that detect functional brain changes in AD. This subset of genes was incorporated into adORS to assess, in comparison to PRS, the prediction accuracy of CN vs. AD classification and MCI conversion prediction, risk stratification of the ADNI cohort, and interpretability of the genetic information included in the scores. Results: adORS improved AUC scores over PRS in both CN vs. AD classification and MCI conversion prediction. The oligogenic model also refined risk-based stratification, even without the assistance of APOE, thus reflecting the true prevalence rate of the ADNI cohort compared to PRS. Interpretation analysis shows that genes included in adORS, such as ATF6, EFCAB11, ING5, SIK3, and CD46, have been observed in similar neurodegenerative disorders and/or are supported by AD-related literature. Discussion: Compared to conventional PRS, adORS may prove to be a more appropriate choice of differentiating patients into high or low genetic risk of AD in clinical studies or settings. Additionally, the ability to interpret specific genetic information allows the focus to be shifted from general relative risk based on a given population to the information that adORS can provide for a single individual, thus permitting the possibility of personalized treatments for AD.Item Artificial intelligence reveals features associated with breast cancer neoadjuvant chemotherapy responses from multi-stain histopathologic images(Springer Nature, 2023-01-27) Huang, Zhi; Shao, Wei; Han, Zhi; Alkashash, Ahmad Mahmoud; De la Sancha, Carlo; Parwani, Anil V.; Nitta, Hiroaki; Hou, Yanjun; Wang, Tongxin; Salama, Paul; Rizkalla, Maher; Zhang, Jie; Huang, Kun; Li, Zaibo; Electrical and Computer Engineering, School of Engineering and TechnologyAdvances in computational algorithms and tools have made the prediction of cancer patient outcomes using computational pathology feasible. However, predicting clinical outcomes from pre-treatment histopathologic images remains a challenging task, limited by the poor understanding of tumor immune micro-environments. In this study, an automatic, accurate, comprehensive, interpretable, and reproducible whole slide image (WSI) feature extraction pipeline known as, IMage-based Pathological REgistration and Segmentation Statistics (IMPRESS), is described. We used both H&E and multiplex IHC (PD-L1, CD8+, and CD163+) images, investigated whether artificial intelligence (AI)-based algorithms using automatic feature extraction methods can predict neoadjuvant chemotherapy (NAC) outcomes in HER2-positive (HER2+) and triple-negative breast cancer (TNBC) patients. Features are derived from tumor immune micro-environment and clinical data and used to train machine learning models to accurately predict the response to NAC in breast cancer patients (HER2+ AUC = 0.8975; TNBC AUC = 0.7674). The results demonstrate that this method outperforms the results trained from features that were manually generated by pathologists. The developed image features and algorithms were further externally validated by independent cohorts, yielding encouraging results, especially for the HER2+ subtype.Item Association between Serum IGF-I levels and Postoperative Delirium in Elderly Subjects Undergoing Elective Knee Arthroplasty.(NPG, 2016) Yen, Timothy E.; Allen, John C.; Rivelli, Sarah K.; Patterson, Stephanie C.; Metcalf, Meredith R.; Flink, Benjamin J.; Mirrakhimov, Aibek E.; Lagoo, Sandhya A.; Vail, Thomas P.; Young, Christopher C.; Moon, Richard E.; Trzepacz, Paula T.; Kwatra, Madan M.; Department of Psychiatry, IU School of MedicineEvidence is mixed for an association between serum insulin-like growth factor-I (IGF-I) levels and postoperative delirium (POD). The current study assessed preoperative serum IGF-I levels as a predictor of incident delirium in non-demented elderly elective knee arthroplasty patients. Preoperative serum levels of total IGF-I were measured using a commercially available Human IGF-I ELISA kit. POD incidence and severity were determined using DSM-IV criteria and the Delirium Rating Scale-Revised-98 (DRS-R98), respectively. Median IGF-I levels in delirious (62.6 ng/ml) and non-delirious groups (65.9 ng/ml) were not significantly different (p = 0.141). The ratio (95% CI) of geometric means, D/ND, was 0.86 (0.70, 1.06). The Hodges-Lehmann median difference estimate was 7.23 ng/mL with 95% confidence interval (−2.32, 19.9). In multivariate logistic regression analysis IGF-I level was not a significant predictor of incident POD after correcting for medical comorbidities. IGF-I levels did not correlate withItem Author Correction: Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations(Springer Nature, 2023-10-19) Feofanova, Elena V.; Brown, Michael R.; Alkis, Taryn; Manuel, Astrid M.; Li, Xihao; Tahir, Usman A.; Li, Zilin; Mendez, Kevin M.; Kelly, Rachel S.; Qi, Qibin; Chen, Han; Larson, Martin G.; Lemaitre, Rozenn N.; Morrison, Alanna C.; Grieser, Charles; Wong, Kari E.; Gerszten, Robert E.; Zhao, Zhongming; Lasky-Su, Jessica; NHLBI Trans-Omics for Precision Medicine (TOPMed); Yu, Bing; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthCorrection to: Nature Communications 10.1038/s41467-023-38800-2, published online 30 May2023 In this article, the author name Robert E. Gerszten was incorrectly written as Robert E. Gersztern. The original article has been corrected.Item Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients(Springer Nature, 2022) Quintanilha, Julia C.F.; Wang, Jin; Sibley, Alexander B.; Jiang, Chen; Etheridge, Amy S.; Shen, Fei; Jiang, Guanglong; Mulkey, Flora; Patel, Jai N.; Hertz, Daniel L.; Dees, Elizabeth Claire; McLeod, Howard L.; Bertagnolli, Monica; Rugo, Hope; Kindler, Hedy L.; Kelly, William Kevin; Ratain, Mark J.; Kroetz, Deanna L.; Owzar, Kouros; Schneider, Bryan P.; Lin, Danyu; Innocenti, Federico; Medicine, School of MedicineBackground: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. Methods: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. Results: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). Conclusions: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension.Item Biomarkers of Oxidative Stress and Endogenous Antioxidants for Patients with Chronic Subjective Dizziness(Nature Research, 2020-01-30) Fang, Zhigang; Huang, Keer; Gil, Chang-Hyun; Jeong, Jin-Woo; Yoo, Ho-Ryong; Kim, Hyeong-Geug; Biochemistry and Molecular Biology, School of MedicineAs a neurotologic disorder of persistent non-vertiginous dizziness, chronic subjective dizziness (CSD) arises unsteadily by psychological and physiological imbalance. The CSD is hypersensitivity reaction due to exposure to complex motions visual stimuli. However, the pathophysiological features and mechanism of the CSD still remains unclearly. The present study was purposed to establish possible endogenous contributors of the CSD using serum samples from patients with the CSD. A total 199 participants were gathered and divided into two groups; healthy (n = 152, male for 61, and female for 91) and CSD (n = 47, male for 5, female for 42), respectively. Oxidative stress parameters such as, hydrogen peroxide and reactive substances were significantly elevated (p < 0.01 or p < 0.001), whereas endogenous antioxidant components including total glutathione contents, and activities of catalase and superoxide dismutase were significantly deteriorated in the CSD group (p < 0.01 or p < 0.001) as comparing to the healthy group, respectively. Serum levels of tumor necrosis factor -α and interferon-γ were significantly increased in the CSD participants (p < 0.001). Additionally, emotional stress related hormones including cortisol, adrenaline, and serotonin were abnormally observed in the serum levels of the CSD group (p < 0.01 or p < 0.001). Our results confirmed that oxidative stress and antioxidants are a critical contributor of pathophysiology of the CSD, and that is first explored to establish features of redox system in the CSD subjects compared to a healthy population.Item Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs(Nature Publishing Group, 2019-12-02) Niculescu, A. B.; Le-Niculescu, H.; Roseberry, K.; Wang, S.; Hart, J.; Kaur, A.; Robertson, H.; Jones, T.; Strasburger, A.; Williams, A.; Kurian, S. M.; Lamb, B.; Shekhar, A.; Lahiri, D. K.; Saykin, A. J.; Psychiatry, School of MedicineShort-term memory dysfunction is a key early feature of Alzheimer’s disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).Item Correction: Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients(Springer Nature, 2022) Quintanilha, Julia C.F.; Wang, Jin; Sibley, Alexander B.; Jiang, Chen; Etheridge, Amy S.; Shen, Fei; Jiang, Guanglong; Mulkey, Flora; Patel, Jai N.; Hertz, Daniel L.; Dees, Elizabeth Claire; McLeod, Howard L.; Bertagnolli, Monica; Rugo, Hope; Kindler, Hedy L.; Kelly, William Kevin; Ratain, Mark J.; Kroetz, Deanna L.; Owzar, Kouros; Schneider, Bryan P.; Lin, Danyu; Innocenti, Federico; Medicine, School of MedicineCorrection to: British Journal of Cancer 10.1038/s41416-021-01557-w, published online 06 October 2021 The original version of this article unfortunately contained a mistake in an author affiliation. Dr. Kouros Owzar was listed as “Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA”, when it should be “Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA”. The original article has been corrected.Item Correction: Neural correlates of automatic emotion regulation and their association with suicidal ideation in adolescents during the first 90-days of residential care(Springer Nature, 2024-02-19) Dobbertin, Matthew; Blair, Karina S.; Aloi, Joseph; Bajaj, Sahil; Bashford-Largo, Johannah; Mathur, Avantika; Zhang, Ru; Carollo, Erin; Schwartz, Amanda; Elowsky, Jaimie; Ringle, J. L.; Tyler, Patrick; Blair, R. James; Psychiatry, School of MedicineCorrection to: Translational Psychiatry 10.1038/s41398-023-02723-9, published online 23 January 2024 In this article, the affiliation details for Author Sahil Bajaj were incorrectly given as “Department of Cancer Systems Imaging, MD Anderson Center, South Campus Research Bldg, Houston, TX, USA” but should have been “Department of Cancer Systems Imaging, MD Anderson Cancer Center, Houston, TX, USA” The original article has been corrected.