Browsing by Subject "Personalized medicine"
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Item Choices in hemodialysis therapies: variants, personalized therapy and application of evidence-based medicine(Oxford University Press, 2021-12-27) Canaud, Bernard; Stuard, Stefano; Laukhuf, Frank; Yan, Grace; Gomez Canabal, Maria Ines; Lim, Paik Seong; Kraus, Michael A.; Medicine, School of MedicineThe extent of removal of the uremic toxins in hemodialysis (HD) therapies depends primarily on the dialysis membrane characteristics and the solute transport mechanisms involved. While designation of ‘flux’ of membranes as well toxicity of compounds that need to be targeted for removal remain unresolved issues, the relative role, efficiency and utilization of solute removal principles to optimize HD treatment are better delineated. Through the combination and intensity of diffusive and convective removal forces, levels of concentrations of a broad spectrum of uremic toxins can be lowered significantly and successfully. Extended clinical experience as well as data from several clinical trials attest to the benefits of convection-based HD treatment modalities. However, the mode of delivery of HD can further enhance the effectiveness of therapies. Other than treatment time, frequency and location that offer clinical benefits and increase patient well-being, treatment- and patient-specific criteria may be tailored for the therapy delivered: electrolytic composition, dialysate buffer and concentration and choice of anticoagulating agent are crucial for dialysis tolerance and efficacy. Evidence-based medicine (EBM) relies on three tenets, i.e. clinical expertise (i.e. doctor), patient-centered values (i.e. patient) and relevant scientific evidence (i.e. science), that have deviated from their initial aim and summarized to scientific evidence, leading to tyranny of randomized controlled trials. One must recognize that practice patterns as shown by Dialysis Outcomes and Practice Patterns Study and personalization of HD care are the main driving force for improving outcomes. Based on a combination of the three pillars of EBM, and particularly on bedside patient–clinician interaction, we summarize what we have learned over the last 6 decades in terms of best practices to improve outcomes in HD patients. Management of initiation of dialysis, vascular access, preservation of kidney function, selection of biocompatible dialysers and use of dialysis fluids of high microbiological purity to restrict inflammation are just some of the approaches where clinical experience is vital in the absence of definitive scientific evidence. Further, HD adequacy needs to be considered as a broad and multitarget approach covering not just the dose of dialysis provided, but meeting individual patient needs (e.g. fluid volume, acid–base, blood pressure, bone disease metabolism control) through regular assessment—and adjustment—of a series of indicators of treatment efficiency. Finally, in whichever way new technologies (i.e. artificial intelligence, connected health) are embraced in the future to improve the delivery of dialysis, the human dimension of the patient–doctor interaction is irreplaceable. Kidney medicine should remain ‘an art’ and will never be just ‘a science’.Item Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers(Impact Journals, 2016-08-30) Radovich, Milan; Kiel, Patrick J.; Nance, Stacy M.; Niland, Erin E.; Parsley, Megan E.; Ferguson, Meagan E.; Jiang, Guanglong; Ammakkanavar, Natraj R.; Einhorn, Lawrence H.; Cheng, Liang; Nassiri, Mehdi; Davidson, Darrell D.; Rushing, Daniel A.; Loehrer, Patrick J.; Pili, Roberto; Hanna, Nasser; Callaghan, J. Thomas; Skaar, Todd C.; Helft, Paul R.; Shahda, Safi; O’Neil, Bert H.; Schneider, Bryan P.; Medicine, School of MedicinePatients and methods: Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. Results: From April 2014-October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). Conclusion: Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy.Item Clinical Genetic and Genomic Testing in Congenital Heart Disease and Cardiomyopathy(MDPI, 2024-04-26) Pidaparti, Mahati; Geddes, Gabrielle C.; Durbin, Matthew D.; Pediatrics, School of MedicineCongenital heart disease (CHD) and cardiomyopathies are the leading cause of morbidity and mortality worldwide. These conditions are often caused by genetic factors, and recent research has shown that genetic and genomic testing can provide valuable information for patient care. By identifying genetic causes, healthcare providers can screen for other related health conditions, offer early interventions, estimate prognosis, select appropriate treatments, and assess the risk for family members. Genetic and genomic testing is now the standard of care in patients with CHD and cardiomyopathy. However, rapid advances in technology and greater availability of testing options have led to changes in recommendations for the most appropriate testing method. Several recent studies have investigated the utility of genetic testing in this changing landscape. This review summarizes the literature surrounding the clinical utility of genetic evaluation in patients with CHD and cardiomyopathy.Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors(Wiley, 2015-08) Hicks, J. Kevin; Bishop, Jeffrey R.; Sangkuhl, Katrin; Müller, Daniel J; Ji, Yuan; Leckband, Susan G.; Leeder, J. Steven; Graham, Rebecca L.; Chiulli, Dana L.; LLerena, Adrián; Skaar, Todd C.; Scott, Stuart A.; Stingl, Julia C.; Klein, Teri E.; Caudle, Kelly E.; Gaedigk, Andrea; Department of Medicine, IU School of MedicineSelective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).Item Computational biology approaches in drug repurposing and gene essentiality screening(2016-06-20) Philips, Santosh; Li, Lang; Liu, Yunlong; Liu, Xiaowen; Skaar, Todd C.; Janga, Sarath C.The rapid innovations in biotechnology have led to an exponential growth of data and electronically accessible scientific literature. In this enormous scientific data, knowledge can be exploited, and novel discoveries can be made. In my dissertation, I have focused on the novel molecular mechanism and therapeutic discoveries from big data for complex diseases. It is very evident today that complex diseases have many factors including genetics and environmental effects. The discovery of these factors is challenging and critical in personalized medicine. The increasing cost and time to develop new drugs poses a new challenge in effectively treating complex diseases. In this dissertation, we want to demonstrate that the use of existing data and literature as a potential resource for discovering novel therapies and in repositioning existing drugs. The key to identifying novel knowledge is in integrating information from decades of research across the different scientific disciplines to uncover interactions that are not explicitly stated. This puts critical information at the fingertips of researchers and clinicians who can take advantage of this newly acquired knowledge to make informed decisions. This dissertation utilizes computational biology methods to identify and integrate existing scientific data and literature resources in the discovery of novel molecular targets and drugs that can be repurposed. In chapters 1 of my dissertation, I extensively sifted through scientific literature and identified a novel interaction between Vitamin A and CYP19A1 that could lead to a potential increase in the production of estrogens. Further in chapter 2 by exploring a microarray dataset from an estradiol gene sensitivity study I was able to identify a potential novel anti-estrogenic indication for the commonly used urinary analgesic, phenazopyridine. Both discoveries were experimentally validated in the laboratory. In chapter 3 of my dissertation, through the use of a manually curated corpus and machine learning algorithms, I identified and extracted genes that are essential for cell survival. These results brighten the reality that novel knowledge with potential clinical applications can be discovered from existing data and literature by integrating information across various scientific disciplines.Item Functional interpretation, cataloging, and analysis of 1,341 glucose-6-phosphate dehydrogenase variants(Elsevier, 2023) Geck, Renee C.; Powell, Nicholas R.; Dunham, Maitreya J.; Medicine, School of MedicineGlucose-6-phosphate dehydrogenase (G6PD) deficiency affects over 500 million individuals who can experience anemia in response to oxidative stressors such as certain foods and drugs. Recently, the World Health Organization (WHO) called for revisiting G6PD variant classification as a priority to implement genetic medicine in low- and middle-income countries. Toward this goal, we sought to collect reports of G6PD variants and provide interpretations. We identified 1,341 G6PD variants in population and clinical databases. Using the ACMG standards and guidelines for the interpretation of sequence variants, we provided interpretations for 268 variants, including 186 variants that were not reported or of uncertain significance in ClinVar, bringing the total number of variants with non-conflicting interpretations to 400. For 414 variants with functional or clinical data, we analyzed associations between activity, stability, and current classification systems, including the new 2022 WHO classification. We corroborated known challenges with classification systems, including phenotypic variation, emphasizing the importance of comparing variant effects across individuals and studies. Biobank data made available by All of Us illustrate the benefit of large-scale sequencing and phenotyping by adding additional support connecting variants to G6PD-deficient anemia. By leveraging available data and interpretation guidelines, we created a repository for information on G6PD variants and nearly doubled the number of variants with clinical interpretations. These tools enable better interpretation of G6PD variants for the implementation of genetic medicine.Item Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans(Springer Nature, 2022-07-05) Lai, Dongbing; Schwantes-An, Tae-Hwi; Abreu, Marco; Chan, Grace; Hesselbrock, Victor; Kamarajan, Chella; Liu, Yunlong; Meyers, Jacquelyn L.; Nurnberger, John I., Jr.; Plawecki, Martin H.; Wetherill, Leah; Schuckit, Marc; Zhang, Pengyue; Edenberg, Howard J.; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineGenome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E-05 to 6.27E-03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E-03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32-2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.Item Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum(Springer Nature, 2024-10-05) Wen, Junhao; Yang, Zhijian; Nasrallah, Ilya M.; Cui, Yuhan; Erus, Guray; Srinivasan, Dhivya; Abdulkadir, Ahmed; Mamourian, Elizabeth; Hwang, Gyujoon; Singh, Ashish; Bergman, Mark; Bao, Jingxuan; Varol, Erdem; Zhou, Zhen; Boquet-Pujadas, Aleix; Chen, Jiong; Toga, Arthur W.; Saykin, Andrew J.; Hohman, Timothy J.; Thompson, Paul M.; Villeneuve, Sylvia; Gollub, Randy; Sotiras, Aristeidis; Wittfeld, Katharina; Grabe, Hans J.; Tosun, Duygu; Bilgel, Murat; An, Yang; Marcus, Daniel S.; LaMontagne, Pamela; Benzinger, Tammie L.; Heckbert, Susan R.; Austin, Thomas R.; Launer, Lenore J.; Espeland, Mark; Masters, Colin L.; Maruff, Paul; Fripp, Jurgen; Johnson, Sterling C.; Morris, John C.; Albert, Marilyn S.; Bryan, R. Nick; Resnick, Susan M.; Ferrucci, Luigi; Fan, Yong; Habes, Mohamad; Wolk, David; Shen, Li; Shou, Haochang; Davatzikos, Christos; Radiology and Imaging Sciences, School of MedicineAlzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .Item Genome Editing and Induced Pluripotent Stem Cell Technologies for Personalized Study of Cardiovascular Diseases(Springer Nature, 2018-04-17) Chun, Young Wook; Durbin, Matthew D.; Hong, Charles C.; Pediatrics, School of MedicinePURPOSE OF REVIEW: The goal of this review is to highlight the potential of induced pluripotent stem cell (iPSC)-based modeling as a tool for studying human cardiovascular diseases. We present some of the current cardiovascular disease models utilizing genome editing and patient-derived iPSCs. RECENT FINDINGS: The incorporation of genome-editing and iPSC technologies provides an innovative research platform, providing novel insight into human cardiovascular disease at molecular, cellular, and functional level. In addition, genome editing in diseased iPSC lines holds potential for personalized regenerative therapies. The study of human cardiovascular disease has been revolutionized by cellular reprogramming and genome editing discoveries. These exceptional technologies provide an opportunity to generate human cell cardiovascular disease models and enable therapeutic strategy development in a dish. We anticipate these technologies to improve our understanding of cardiovascular disease pathophysiology leading to optimal treatment for heart diseases in the future.Item Impacts of biomedical hashtag-based Twitter campaign: #DHPSP utilization for promotion of open innovation in digital health, patient safety, and personalized medicine(Elsevier, 2021) Kletecka-Pulker, Maria; Mondal, Himel; Wang, Dongdong; Parra, R. Gonzalo; Maigoro, Abdulkadir Yusif; Lee, Soojin; Garg, Tushar; Mulholland, Eoghan J.; Devkota, Hari Prasad; Konwar, Bikramjit; Patnaik, Sourav S.; Lordan, Ronan; Nawaz, Faisal A.; Tsagkaris, Christos; Rayan, Rehab A.; Louka, Anna Maria; De, Ronita; Badhe, Pravin; Schaden, Eva; Willschke, Harald; Maleczek, Mathias; Boyina, Hemanth Kumar; Khalid, Garba M.; Uddin, Md. Sahab; Sanusi; Khan, Johra; Odimegwu, Joy I.; Yeung, Andy Wai Kan; Akram, Faizan; Sai, Chandragiri Siva; Bucher, Sherri; Paswan, Shravan Kumar; Singla, Rajeev K.; Shen, Bairong; Di Lonardo, Sara; Tosevska, Anela; Simal-Gandara, Jesus; Zec, Manja; González-Burgos, Elena; Habijan, Marija; Battino, Maurizio; Giampieri, Francesca; Tikhonov, Aleksei; Cianciosi, Danila; Forbes-Hernandez, Tamara Y.; Quiles, José L.; Mezzetti, Bruno; Babiaka, Smith B.; Ahmed, Mosa E. O.; Piccard, Paula; Urquiza, Mágali S.; Depew, Jennifer R.; Schultz, Fabien; Sur, Daniel; Pai, Sandeep R.; Găman, Mihnea-Alexandru; Cenanovic, Merisa; Tzvetkov, Nikolay T.; Tripathi, Surya Kant; Kharat, Kiran R.; Garcia-Sosa, Alfonso T.; Sieber, Simon; Atanasov, Atanas G.; Pediatrics, School of MedicineThe open innovation hub Digital Health and Patient Safety Platform (DHPSP) was recently established with the purpose to invigorate collaborative scientific research and the development of new digital products and personalized solutions aiming to improve human health and patient safety. In this study, we evaluated the effectiveness of a Twitter-based campaign centered on using the hashtag #DHPSP to promote the visibility of the DHPSP initiative. Thus, tweets containing #DHPSP were monitored for five weeks for the period 20.10.2020–24.11.2020 and were analyzed with Symplur Signals (social media analytics tool). In the study period, a total of 11,005 tweets containing #DHPSP were posted by 3020 Twitter users, generating 151,984,378 impressions. Analysis of the healthcare stakeholder-identity of the Twitter users who used #DHPSP revealed that the most of participating user accounts belonged to individuals or doctors, with the top three user locations being the United States (501 users), the United Kingdom (155 users), and India (121 users). Analysis of co-occurring hashtags and the full text of the posted tweets further revealed that the major themes of attention in the #DHPSP Twitter-community were related to the coronavirus disease 2019 (COVID-19), medicine and health, digital health technologies, and science communication in general. Overall, these results indicate that the #DHPSP initiative achieved high visibility and engaged a large body of Twitter users interested in the DHPSP focus area. Moreover, the conducted campaign resulted in an increase of DHPSP member enrollments and website visitors, and new scientific collaborations were formed. Thus, Twitter campaigns centered on a dedicated hashtag prove to be a highly efficient tool for visibility-promotion, which could be successfully utilized by healthcare-related open innovation platforms or initiatives.