Investigating the Genetic Profile of the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS-FTD) Continuum in Patients of Diverse Race, Ethnicity and Ancestry

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 76
Author(s):  
Maysen Mesaros ◽  
Steven Lenz ◽  
Woobeen Lim ◽  
Jordan Brown ◽  
Luke Drury ◽  
...  

Preliminary evidence suggests that commonly used genetic tests may be less likely to identify a genetic etiology for ALS-FTD in patients of underrepresented race, ethnicity, and ancestry (REA), as compared to European REA. Patients of underrepresented REA may therefore be less likely to receive accurate and specific genetic counseling information and less likely to have access to gene-targeted therapies currently in clinical trials. We compiled outcome data from 1911 ALS-FTD patients tested at a commercial laboratory over a seven-year period for C9orf72 hexanucleotide repeat expansion (HRE) alone or C9orf72 and multigene sequencing panel testing. We compared the incidence of pathogenic (P), likely pathogenic (LP), and uncertain variants in C9orf72 and other ALS-FTD genes, as well as age at testing, in patients of different REA. The diagnostic rate in patients of European REA (377/1595, 23.64%) was significantly higher than in patients of underrepresented REA (44/316, 13.92%) (p < 0.001). Patients of European REA were more likely to have the C9orf72 HRE (21.3%) than patients of underrepresented REA (10.4%) (p < 0.001). The overall distribution of positive test outcomes in all tested genes was significantly different between the two groups, with relatively more P and LP variants in genes other than C9orf72 identified in patients of underrepresented REA. The incidence of uncertain test outcomes was not significantly different between patients of European and underrepresented REA. Patients with positive test outcomes were more likely to be younger than those with negative or uncertain outcomes. Although C9orf72 HRE assay has been advocated as the first, and in some cases, only genetic test offered to patients with ALS-FTD in the clinical setting, this practice may result in the reduced ascertainment of genetic ALS-FTD in patients of diverse REA.

2021 ◽  
pp. 0272989X2110027
Author(s):  
Frederik van Delft ◽  
Mirte Muller ◽  
Rom Langerak ◽  
Hendrik Koffijberg ◽  
Valesca Retèl ◽  
...  

Background Although immunotherapy (IMT) provides significant survival benefits in selected patients, approximately 10% of patients experience (serious) immune-related adverse events (irAEs). The early detection of adverse events will prevent irAEs from progressing to severe stages, and routine testing for irAEs has become common practice. Because a positive test outcome might indicate a clinically manifesting irAE that requires treatment to (temporarily) discontinue, the occurrence of false-positive test outcomes is expected to negatively affect treatment outcomes. This study explores how the UPPAAL modeling environment can be used to assess the impact of test accuracy (i.e., test sensitivity and specificity), on the probability of patients entering palliative care within 11 IMT cycles. Methods A timed automata-based model was constructed using real-world data and expert consultation. Model calibration was performed using data from 248 non–small-cell lung cancer patients treated with nivolumab. A scenario analysis was performed to evaluate the effect of changes in test accuracy on the probability of patients transitioning to palliative care. Results The constructed model was used to estimate the cumulative probabilities for the patients’ transition to palliative care, which were found to match real-world clinical observations after model calibration. The scenario analysis showed that the specificity of laboratory tests for routine monitoring has a strong effect on the probability of patients transitioning to palliative care, whereas the effect of test sensitivity was limited. Conclusion We have obtained interesting insights by simulating a care pathway and disease progression using UPPAAL. The scenario analysis indicates that an increase in test specificity results in decreased discontinuation of treatment due to suspicion of irAEs, through a reduction of false-positive test outcomes.


2017 ◽  
pp. 1-7 ◽  
Author(s):  
Mary Helen Black ◽  
Shuwei Li ◽  
Tina Pesaran ◽  
Holly LaDuca ◽  
Rachid Karam ◽  
...  

Purpose PTEN mutations are associated with breast, colon, endometrial, kidney, and thyroid cancers. Most PTEN promoter alterations, however, are characterized as variants of unknown significance, and their contribution to cancer risk is unclear. Materials and Methods Personal and family histories of 88,333 patients undergoing PTEN analysis as part of multigene panel testing (MGPT) were retrospectively reviewed. Cases (n = 59,784) were individuals with personal history of PTEN-related cancer. Controls (n = 28,549) had no personal history of cancer. Individuals were categorized as positive for one or more mutations (PATHO), without mutations but carrying one or more promoter variant (PROM), or negative for alterations (WT). Multivariable logistic regression was used to assess PTEN associations with phenotypes, adjusted for race/ethnicity, age, sex, and MGPT. Results Overall, 79 (0.09%) patients were PATHO and 791 (0.9%) were PROM carriers. Compared with WT, PATHOs were 2.30 (95% CI, 1.19 to 4.72) times as likely to have breast, 7.23 (95% CI, 2.74 to 19.14) times as likely to have bilateral/multiple primary breast, and 7.56 (95% CI, 1.97 to 23.98) times as likely to have uterine/endometrial cancer. PROMs were not significantly more likely than WT to have cancer (all 0.84 < odds ratio < 1.15; P > .05). Conclusion PTEN promoter variants were not associated with cancer. These results do not support the inclusion of PTEN promoter sequencing in MGPT.


2019 ◽  
Vol 27 (4) ◽  
pp. 594-616 ◽  
Author(s):  
Guy C. Wilson ◽  
Yorgi Mavros ◽  
Lotti Tajouri ◽  
Maria Fiatarone Singh

Background:Variations in genotype may contribute to heterogeneity in functional adaptations to exercise.Methods:A systematic search of eight databases was conducted, and 9,696 citations were screened.Results:Eight citations from seven studies measuring 10 single-nucleotide polymorphisms and nine different functional performance test outcomes were included in the review. There was one observational study of physical activity and six experimental studies of aerobic or resistance training. The ACE (D) allele, ACTN3 (RR) genotype, UCP2 (GG) genotype, IL-6-174 (GG) genotype, TNF-α-308 (GG) genotype, and IL-10-1082 (GG) genotype all predicted significantly superior adaptations in at least one functional outcome in older men and women after prescribed exercise or in those with higher levels of physical activity.Conclusion:There is a small amount of evidence that older adults may have better functional outcomes after exercise/physical activity if they have specific alleles related to musculoskeletal function or inflammation. However, more robust trials are needed.


2018 ◽  
Vol 40 (3) ◽  
pp. 420-445 ◽  
Author(s):  
Jennifer L. Steele ◽  
Robert O. Slater ◽  
Jennifer Li ◽  
Gema Zamarro ◽  
Trey Miller ◽  
...  

Using input and outcome data from a randomized study of dual-language immersion programs in an urban district, we examine the mediating relationships of dosage, expenditures, and classroom characteristics to students’ academic performance, and the moderating role of students’ race/ethnicity. Differential costs of immersion were concentrated at the district level and were modest, at about 2% to 4% of per-pupil spending annually. We estimate that an additional US$100 spent per immersion student in a given year was associated with an additional 8% of a standard deviation in language arts performance in English, which was just over one third of the causal point-in-time enrollment effect of 22% of a standard deviation. We find no generalizable evidence of differential effects by race/ethnicity.


2021 ◽  
Vol 7 (5) ◽  
pp. e615
Author(s):  
Jennifer Roggenbuck ◽  
Kelly A. Rich ◽  
Leah Vicini ◽  
Marilly Palettas ◽  
Joceyln Schroeder ◽  
...  

ObjectiveTo report the frequency of amyotrophic lateral sclerosis (ALS) genetic variants in a nationwide cohort of clinic-based patients with ALS with a family history of ALS (fALS), dementia (dALS), or both ALS and dementia (fALS/dALS).MethodsA multicenter, prospective cohort of 573 patients with fALS, dALS, or fALS/dALS, underwent genetic testing in the ALS Genetic Access Program (ALS GAP), a clinical program for clinics of the Northeast ALS Consortium. Patients with dALS underwent C9orf72 hexanucleotide repeat expansion (HRE) testing; those with fALS or fALS/dALS underwent C9orf72 HRE testing, followed by sequencing of SOD1, FUS, TARDBP, TBK1, and VCP.ResultsA pathogenic (P) or likely pathogenic (LP) variant was identified in 171/573 (30%) of program participants. About half of patients with fALS or fALS/dALS (138/301, 45.8%) had either a C9orf72 HRE or a P or LP variant identified in SOD1, FUS, TARDBP, TBK1, or VCP. The use of a targeted, 5-gene sequencing panel resulted in far fewer uncertain test outcomes in familial cases compared with larger panels used in other in clinic-based cohorts. Among dALS cases 11.8% (32/270) were found to have the C9orf72 HRE. Patients of non-Caucasian geoancestry were less likely to test positive for the C9orf72 HRE, but were more likely to test positive on panel testing, compared with those of Caucasian ancestry.ConclusionsThe ALS GAP program provided a genetic diagnosis to ∼1 in 3 participants and may serve as a model for clinical genetic testing in ALS.


2008 ◽  
Vol 9 (2) ◽  
pp. 42-50 ◽  
Author(s):  
Richard T. Meenan ◽  
David Feeny ◽  
David Labby ◽  
Mark Spofford ◽  
David Mosen ◽  
...  

CareOregon, an Oregon-based not-for-profit Medicaid health plan, successfully piloted a “CareSupport” model that identifies high-risk members and clinically stratifies them for intervention. Internal analyses indicate that CareSupport lowers utilization and cost; CareOregon, however, has lacked patient-reported outcome data on the health-related quality of life (HRQL) of CareSupport participants. Between September 2005 and November 2006, we conducted a pilot study in which the Health Utilities Index Mark 3 (HUI3), a generic preference-based measure of health status and HRQL, was integrated into CareOregon’s existing screening algorithm for possible admission into CareSupport. We obtained baseline data on 616 CareSupport candidates and 4-month HUI3 follow-up data on 143 candidates (104 CareSupport, 39 non-CareSupport). On a 0.00 (dead)-to-1.00 (perfect health) scale, the mean overall baseline HUI3 score for CareSupport patients was 0.18 (0.20 for non-CareSupport patients), comparable to baseline means reported elsewhere for much older patients immediately after suffering serious acute medical events, such as stroke or hip fracture. A 0.05 mean 4-month improvement in overall HRQL among CareSupport enrollees relative to non-CareSupport enrollees was clinically important but not statistically significant. A 0.10 improvement in HUI3 emotion was both statistically significant and clinically important. Study results provide good preliminary evidence of the value of patient-reported outcomes in clarifying individual illness burden and assessing intervention effectiveness.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1538-1538
Author(s):  
Kristen Danielle Whitaker ◽  
Ryan Bernhisel ◽  
John Kidd ◽  
Elisha Hughes ◽  
Eric Thomas Rosenthal ◽  
...  

1538 Background: BRIP1/ FANCJ participates in DNA replication and repair via interactions with BRCA1 and possibly MLH1. Previous studies have reported that pathogenic variants (PV) in BRIP1 are associated with an ~2-fold increase in risk for ovarian cancer (OC) and triple-negative breast cancer (TNBC). Although multigene panel testing for hereditary cancer (CA) has identified BRIP1 PV and uncertain variants (VUS) in patients with diverse CAs including breast (BC), colorectal (CRC) and melanoma (Mel), association with these CA types has not been established. Methods: We examined BRIP1 risks in two independent populations: Fox Chase Cancer Center (FCCC) and Myriad Genetics (MGL). At FCCC, pedigrees of BRIP1 PV ( N= 10) and VUS families ( N= 47) were reviewed. The MGL population included patients referred for testing by multigene panel (9/2013-12/2019) ( N= 586,740). Multivariable logistic regression analysis estimated BRIP1 CA risks as odds ratios (ORs) and 95% confidence intervals (CIs). Models were adjusted for age, sex, ancestry, personal CA history (PHX), and family CA history. Results: In the FCCC cohort, BRIP1 PV carriers ( N= 12) reported PHX of early-onset ( < 50) BC, CRC, and bladder CA. BRIP1 VUS were also identified among several patients with striking PHX and negative panel testing: BC < 40 ( N= 3), bilateral BC ( N= 4), TNBC ( N= 2), CRC < 40 ( N= 3), and a patient with 3 CAs < 40 (CRC, BC, and Mel). All FCCC families with a BRIP1 PV and select VUS families ( N= 6) are seen in the Table. In the MGL population, 0.3% (1,678/586,740) carried a BRIP1 PV. Logistic regression analyses found that female BRIP1 PV carriers have significantly increased risk for OC (OR 2.40, 95% CI 1.93-2.98) and TNBC (OR 1.93, 95% CI 1.52-2.46). Data were insufficient for testing risk of bladder or prostate CA. Findings did not support associations of BRIP1 with CRC, melanoma, endometrial, pancreatic or gastric CA. Conclusions: BRIP1 PV and VUS may be identified in patients with diverse CA histories. These results confirm studies showing that BRIP1 PV are associated with an ~2-fold increased risk of OC and TNBC, but do not support increased risks of CRC, melanoma or endometrial CA in BRIP1 PV carriers. [Table: see text]


PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0244393
Author(s):  
Andrea C. Vial ◽  
Janine Bosak ◽  
Patrick C. Flood ◽  
John F. Dovidio

We theorize that individuals’ pre-existing beliefs about the hiring manager role (role construal) are associated with their tendency to condone bias accommodation in hiring contexts, in which a person aligns hiring decisions with the perceived biases of others. In two studies, we focus on human resources (HR) professionals’ endorsement of the role demand to prioritize candidate fit with others (e.g., supervisor) when making hiring decisions. Study 1 examined bias accommodation from a vicarious perspective, revealing that role demand endorsement is positively associated with viewing it as acceptable and common for another hiring manager to accommodate third-party bias against women. Study 2 examined bias accommodation experimentally from an actor’s perspective, showing lower preference for and selection of a female (vs. male) job candidate in the presence of cues to third-party bias against women, but only when role demand endorsement is relatively high. HR professionals in both studies indicated that third-party bias influences in hiring are relatively common. Responses in Study 2 provide preliminary evidence that the phenomenon of third-party bias accommodation might be relevant in the context of employment discrimination based on group characteristics other than gender (e.g., race/ethnicity, age). We discuss the practical implications of our findings for hiring professionals and for organizations seeking to increase diversity in their workforce.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 501-501
Author(s):  
Precious Esie ◽  
Jennifer Manly ◽  
Justina Avila-Rieger

Abstract State-level labor market disparities have been linked to health outcomes. The current study examines how labor market disparities may shape different patterns of sex/gender inequalities in cognition across race/ethnicity, place, and time. We leverage cognitive outcome data from multiple cohort and nationally representative longitudinal studies, as well as historical data on labor force participation and occupational status from IPUMS CPS. Multilevel modeling analyses was used to examine heterogeneity in sex/gender inequalities in cognitive trajectories within and between race/ethnicity and U.S. state of birth and determine whether such variability is explained by a state-level labor market opportunity composite. We expect women to demonstrate an advantage over men on cognitive measures. Women’s advantage will be more pronounced in states with a small sex/gender gap in labor market opportunities and less pronounced in states with a large gap. The magnitude of this advantage will be greater for White women compared with Black women.


2017 ◽  
Vol 47 (9) ◽  
pp. 1515-1527 ◽  
Author(s):  
J. Firth ◽  
B. Stubbs ◽  
J. Sarris ◽  
S. Rosenbaum ◽  
S. Teasdale ◽  
...  

BackgroundWhen used as an adjunctive with antipsychotics, certain vitamins and minerals may be effective for improving symptomatic outcomes of schizophrenia, by restoring nutritional deficits, reducing oxidative stress, or modulating neurological pathways.MethodWe conducted a systematic review of all randomized controlled trials (RCTs) reporting effects of vitamin and/or mineral supplements on psychiatric symptoms in people with schizophrenia. Random-effects meta-analyses were used to calculate the standardized mean difference between nutrient and placebo treatments.ResultsAn electronic database search in July 2016 identified 18 eligible RCTs, with outcome data for 832 patients. Pooled effects showed that vitamin B supplementation (including B6, B8 and B12) reduced psychiatric symptoms significantly more than control conditions [g= 0.508, 95% confidence interval (CI) 0.01–1.01,p= 0.047,I2= 72.3%]. Similar effects were observed among vitamin B RCTs which used intention-to-treat analyses (g= 0.734, 95% CI 0.00–1.49,p= 0.051). However, no effects of B vitamins were observed in individual domains of positive and negative symptoms (bothp> 0.1). Meta-regression analyses showed that shorter illness duration was associated with greater vitamin B effectiveness (p= 0.001). There were no overall effects from antioxidant vitamins, inositol or dietary minerals on psychiatric symptoms.ConclusionsThere is preliminary evidence that certain vitamin and mineral supplements may reduce psychiatric symptoms in some people with schizophrenia. Further research is needed to examine how the benefits of supplementation relate to nutrient deficits and the impact upon underlying neurobiological pathways, in order to establish optimal nutrient formulations for improving clinical outcomes in this population. Future studies should also explore the effects of combining beneficial nutrients within multi-nutrient formulas.


Sign in / Sign up

Export Citation Format

Share Document