Florida Consortium Research Articles

Targeted plasma eQTL and pQTL to identify potential novel biomarkers for Alzheimer’s Disease in African Americans

AbstractBackgroundGiven the overlap of symptoms between Alzheimer’s disease (AD) and other dementias, it is essential to develop widely accessible biomarkers that will ensure an accurate diagnosis of AD to enable its proper treatment. African Americans (AA) are twice more likely to develop AD than non‐Hispanic whites (NHW) and yet they remain underrepresented in AD research. The few studies conducted in AA suggest that there are different factors that influence AD in this population; therefore, it is possible that different biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study we are testing the hypothesis that genetic variants that show association with AD‐risk in AA and with plasma levels of transcript and proteins may serve as AD biomarkers which are more accessible and less costly than cerebrospinal fluid or neuroimaging biomarkers.MethodsIn 189 AD cases and 183 cognitively unimpaired (CU) AA participants of the Florida Consortium of African American Alzheimer’s Disease Studies (FCA3DS), we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants were tested for association with plasma transcripts and plasma total tau protein levels previously measured in this cohort using a nanoString® custom panel (Reddy J, et al. 2022) and Simoa assays (Deniz K, et al. 2021), respectively. In receiver operating characteristic (ROC) analyses, the most significant expression/protein quantitative trait loci (eQTL/pQTL) were added sequentially to a base model that included only age and sex to identify eQTL/pQTL that improved the accuracy to correctly classify AD cases vs. CU.ResultsOf the 5112 variants identified in the targeted sequencing, 71 were nominally associated (p<0.05) with plasma transcript/protein levels and with AD‐risk. ROC analysis of age, sex, eQTL/pQTL in APOE, ABCA7, AKAP9, EPHA1, SORL1, and TLR4, and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE‐ɛ4 dosage achieved 77.6% area under the curve (AUC) to discriminate AD vs. CU, a 19.9% improvement over a model that only included age and sex.ConclusionsPlasma transcript levels and eQTL/pQTL are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.

Transcript levels in plasma contribute substantial predictive value as potential Alzheimer's disease biomarkers in African Americans.

SummaryBackgroundAfrican Americans (AA) remain underrepresented in Alzheimer's disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer's Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers.MethodUtilizing FCA3DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes.FindingsAssociation with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. Receiver operating characteristic analysis of age, sex APOE-ε4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% area under the curve to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-ε4 dosage.InterpretationIncorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels.FundingThis work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].

Plasma transcript profiling identifies significant differentially expressed genes and expression of quantitative trait loci in African Americans

AbstractBackgroundAfrican Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being ∼2X higher in this population compared to non‐Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing primarily on the identification of genetic risk factors and novel plasma biomarkers.MethodUtilizing plasma samples from FCA3DS AD cases (n=158) and cognitively unimpaired elderly controls (n=272), we have performed differential gene expression (DEG) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom NanoString® panel that we have designed to measure transcript levels in plasma of genes relevant to AD. Transcript counts were determined using the NanoString® nCounter system, following manufacturer’s protocols. Transcript counts from 43 of the 50 customs assays passed pre‐established quality control thresholds and were utilized for the DEG and eQTL analyses. Our published FCA3DS whole exome sequence (WES) data was utilized for the eQTL analyses. Linear mixed models adjusted for relevant biological and technical covariates were implemented with the lme4 package in R software (v3.6.2) for the DEG and eQTL analyses.ResultAn association with higher plasma CLU in controls compared to AD remained significant after Bonferroni correction for the 43 transcripts tested. The eQTL analysis revealed significant association (FDR q‐value<0.05) with 105 WES variants in cis with 22 of 43 genes tested, including variants in genes previously associated with AD risk in AA. ConclusionThe results from this AA plasma eQTL analysis revealed ABCA7 variants that are significantly associated with lower plasma ABCA7 transcript levels. One of the significant plasma ABCA7 eQTLs was previously shown by our group to be associated with increased AD risk in AA, suggesting that this may be a functional eQTL underlying the risk of AD in AA. The association of higher levels of CLU transcript in plasma from controls compared to AD is in line with results published by others which showed that higher baseline concentration of clusterin protein in plasma was associated with slower rates of brain atrophy. These results support plasma transcripts as novel endophenotypes in AD biomarker studies.

Transcript Levels in Plasma Contribute Substantial Predictive Value as Potential Alzheimer's Disease Biomarkers in African Americans

Background: African Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. Method: Utilizing FCA 3 DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. Findings: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. ROC analysis of age, sex APOE-e4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% AUC to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-e4 dosage. Interpretation: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. Funding: National Institute on Aging, Florida Health Ed and Ethel Moore Alzheimer’s Disease grants. Declaration of Interest: None to declare. Ethical Approval: Informed consent and approval by the Mayo Clinic Institutional Review Board was obtained.

Plasma Biomarkers of Alzheimer's Disease in African Americans.

Background/Objective:The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer’s disease (AD) pathology and neuroinflammation are associated with disease status in African Americans.Methods:We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer’s Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations.Results:Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOE ɛ4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42.Conclusion:We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.

Identifying therapeutic targets for Alzheimer's disease with big data.

Nilüfer Ertekin-Taner is a Professor of Neuroscience and Neurology at the Mayo Clinic, Jacksonville, FL, USA. A neurogeneticist and board-certified behavioral neurologist, she received her medical degree from Hacettepe University Medical School in Ankara, Turkey and her doctorate degree in Molecular Neuroscience from Mayo Graduate School. She completed her residency training in the Department of Neurology at Mayo Clinic in Rochester (MN, USA) and fellowship in Behavioral Neurology at Mayo Clinic in Jacksonville. Her laboratory aims to discover and characterize genetic factors underlying the complex genetics of Alzheimer's disease (AD) and related neurodegenerative conditions. Her earlier work contributed to the establishment of the endophenotype approach in genetic studies of AD and pioneered the use of amyloid β peptide levels as an endophenotype in AD genetic research. Her laboratory currently uses biological traits such as gene expression levels and cognitive scores and leverages combined genome, transcriptome and epigenetic data to uncover genetic risk factors for neurodegenerative conditions. She is the principal investigator of numerous NIH and foundation grants. She leads multiple collaborative projects aimed at gene and pathway discoveries in AD and other neurodegenerative diseases, as a part of the NIH initiatives Accelerating Medicines Partnership AD (AMP-AD) and Molecular Mechanisms of the Vascular Etiology of AD (M2OVE-AD) consortia. She is the Principal Investigator of the Florida Consortium for African-American AD Studies (FCA3DS). As a neurologist in the Memory Disorders Clinic at Mayo Clinic in Jacksonville, Florida, she continues to evaluate and manage patients with AD and other dementias and aspires to improve the quality of care that we provide to our patients and their families.

Community College Student Perceptions of Their Experiences Related to Global Learning: Understanding the Impact of Family, Faculty, and the Curriculum

ABSTRACTThe purpose of this mixed-method research study was to better understand community college students’ engagement in global learning. The study, supported by the Florida Consortium for International Education, was conducted during the 2015–2016 academic year in Florida across nine community colleges drawing from a 55-question survey with an 11% response rate (n = 175). Both qualitative and quantitative methods were used, with data analysis conducted using NVivo and SPSS software. An electronic survey was piloted with one institution, and a refined version was sent to select professors across nine community colleges in the state for distribution to students in the fall semester of 2015. A total of 175 students completed the survey. The majority of students responding were interested in global learning; however, they reported that this interest stemmed primarily from family encouragement and personal experiences rather than from their academic experiences. Students did report that professors were promoting global learning in their classes, although the results were not statistically significant. Students who did not express an interest in global learning felt as though it was not important because it was unrelated to their daily lives. It is the hope that this study will inform community college administrators and faculty to better understand how and why students become interested in global learning to more effectively promote their engagement both on and off campus.

Responding to stakeholder's demands for climate information: from research to applications in Florida

Previous research shows that Florida's climate and agricultural production are influenced by the El Niño-Southern Oscillation, suggesting that farmers and ranchers might use new methods of climate forecasting to modify management, increase profits and reduce economic risks. The purposes of this paper are to describe the framework used by a Florida Consortium (FC) of researchers to assess the potential use of climate forecasts in agricultural decision-making and to summarize what was learned in the research process. The framework includes components for generation, communication and use of climate information as well as an implementation and evaluation component. Results showed that winter months are affected most by ENSO phase (higher rainfall and lower temperatures in El Niño years and the opposite during La Niña years). Yields of most crops were significantly associated with ENSO phase as were prices of some commodities. Through various mechanisms of interacting with farmers, ranchers, and extension faculty, we learned that interest in climate forecasts varied widely from highly optimistic to skeptical, and that these clients had good ideas of how to vary management if they have good forecasts. Case studies aimed at understanding potential value and risks associated with use of climate forecasts were conducted for winter fresh market tomato, cow-calf operations, and peanut production. Analytical results, confirmed by interactions with clients, showed significant value in using climate forecasts to alter specific decisions. Risks of using climate information varied among commodities, with considerable risk found in tomato due to the strong link between production and price. Perhaps the most important lesson learned was the importance of engaging trusted advisors in research and outreach efforts. A major output of the project was the close cooperation established between the FC and the Florida Cooperative Extension Service. Prospects for sustaining a climate information program in Florida are high due to joint research and extension initiatives.

Educational technology and distance education in central Florida: An assessment of capabilities

The Faculty Development Group of the Central Florida Consortium of Higher Education (CFCHE) developed a needs assessment to address the capabilities and experience of CFCHE faculty with distance education, educational technologies, and instructional design. Assessment results include 1) the factors perceived by instructors as most important for both promoting and inhibiting the learning of new educational technologies; 2) distance education experience with and interest in various delivery approaches; and 3) the extent to which CFCHE faculty possess the necessary instructional design skills to initiate distance education courses. These results may provide information that is beneficial to institutions planning distance education initiatives.

Recorded Criteria as a “Gold Standard” for Sensitivity and Specificity Estimates of Surveillance of Nosocomial Infection: A Novel Method to Measure Job Performance

To compare the accuracy of infection control practitioners' (ICPs') classifications of operative site infection in Florida Consortium for Infection Control (FCIC) hospitals, in two time periods, 1990 to 1991 and 1991 to 1992, and to estimate the effect of duration of surveillance experience on that accuracy. Medical record reviewers examined records of all patients classified by an ICP as infected, to distinguish false-positives from true infections based on evidence of standard infection criteria and the ICP's contemporaneous clinical observations. Reviewers also examined a random sample of 100 records from patients classified as noninfected for evidence of undetected infections (false-negatives). These observations permitted estimates of the sensitivity and specificity of each ICP's classification of infection status. Fourteen FCIC community hospitals at which performance of 16 ICPs was monitored. There was a strong linear trend relating increasing sensitivity to numbers of years of ICP surveillance experience (P < .001). For ICPs with < 4 years of experience, satisfactory sensitivity (> or = 80%) was reached in only one of 10 ICP-years of observation. For ICPs with > or = 4 years' experience, satisfactory sensitivity was achieved for 14 of 18 person-years (P = .001). Estimated specificity was 97% to 100% for all ICP-years observed. ICPs with < 4 years of surveillance experience in FCIC community hospitals rarely achieved a satisfactory sensitivity estimate, whereas ICPs with > or = 4 years' experience generally did. Monitoring ICP surveillance accuracy through retrospective medical record audits offers an objective approach to evaluating ICP performance and to interpreting infection rates at different hospitals.

Increased Resistance to Cefoxitin and Cefotetan Among Bacteroides fragilis Isolates from Abdominal Sources in Patients Undergoing Surgery

Journal Article Increased Resistance to Cefoxitin and Cefotetan Among Bacteroides fragilis Isolates from Abdominal Sources in Patients Undergoing Surgery Get access N. Joel Ehrenkranz, N. Joel Ehrenkranz Florida Consortium for Infection Control, South Miami, Florida Reprints or correspondence: Dr. N. Joel Ehrenkranz, Florida Consortium for Infection Control, 5901 Southwest 74th Street, Suite 300, South Miami, Florida 33143. Search for other works by this author on: Oxford Academic PubMed Google Scholar Bianca Alfonso Bianca Alfonso Florida Consortium for Infection Control, South Miami, Florida Search for other works by this author on: Oxford Academic PubMed Google Scholar Clinical Infectious Diseases, Volume 17, Issue 6, December 1993, Pages 1080–1081, https://doi.org/10.1093/clinids/17.6.1080-a Published: 01 December 1993