GWAS Indicates the Presence of Rare Immunogenetic Polymorphisms as Possible Predisposition Factors in Aplastic Anemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1093-1093
Author(s):  
Bartlomiej P Przychodzen ◽  
Monika Jasek ◽  
Sandra P Smieszek ◽  
Ron Paquette ◽  
Rainer Richter ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Genetic Variants ◽  
Large Scale ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
New Paradigm ◽  
Genetic Traits ◽  
Network Analyses ◽  
Low Prevalence ◽  
The Impact

Abstract Abstract 1093 Poster Board I-115 While immune mechanisms are involved in the pathogenesis of idiopathic aplastic anemia (AA), due to the impact of exogenous factors and the low prevalence of AA, this disease is not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies such as single nucleotide polymorphism arrays (SNP-A), large scale investigations in various disorders have been conducted. A systems level understanding of particular disease can allows for identification of candidate genetic variants as prognostic and diagnostic markers. We have applied 6.0 SNP-A containing 924644 SNP probes to conduct a comprehensive GWAS in AA with the aim of identifying low prevalence genetic variants that contribute to the pathogenesis of this condition and contribute to individual disease risk. We studied 124 AA patients and significant cohort of 2230 controls that increase detection power using SNP-A. After exclusion of SNP's with call rate of <95% and those with violation of Hardy Weinberg equilibrium (p<.01), 809.802 SNPs (87.5% of initial set) were passed for further investigation. Single allele χ2 statistics for all autosomal markers were performed. 1935 SNP's pointing towards genes with minor allele frequency (MAF) <10% and p<.001 after Bonferroni correction (more stringent than False Discovery Rate) were selected. Of great interest was the top scoring non synonymous SNP (1/38) rs1028180 located in BLZF1 (OR 6.62) involved in cell proliferation and growth. It was represented by singular marker (p<1×10–4) occurring at a heterozygous frequency of 15% vs. 3.5% in controls, and a homozygous frequency of 3.7% vs. 0% in controls. A total of 1 non-synonymous and 3 strongest intronic SNPs were prioritized for final investigation. These included rs9566991, rs1773557 and rs1495963 and directed to informative genes TNFSF11 (OR 6.24), CD247 (OR 3.52) and IL12RB2 (OR 7.04), respectively. Remarkably, several informative LD blocks were identified represented by multiple markers pointing to the presence of informative polymorphisms in the corresponding regions. TNFSF1 gene was represented by marker rs9566991 (p<1×10–3) occurring at the heterozygous frequency of 15.4% vs. 2.7% in controls. The corresponding MAF was 7.6% vs. 1.3%. A second potential locus identified in our study (CD247) was represented by rs1773557 marker (p<1×10–20) occurring at a heterozygous frequency of 19.6% vs. 5.9% in controls, and in homozygous frequency of 0% vs. 0% in controls. Other SNPs including rs1737501, rs1737502 pointed to the same locus. IL12RB2 was represented by a singular marker rs1495963 (p<1×10–6) occurring at the heterozygous frequency of 24% vs. allelic frequency of 3.2% in controls. MAF were 12% versus 1.9%. Another potential loci marked by rs17131583 was TGFBR3. Analysis targeting individual SNP has been the primary focus of GWAS but such an approach offers only limited understanding of the complex diseases as not an individual SNP, and rather a joint action of several SNPs results in particular outcomes. Consequently, in study of AA, we applied the network gene association analysis as a new paradigm incorporating both “operator OR” and “operator AND” thereby allowing for dependence and independence testing. Consequently, the proposed paradigm may lead to identification of meaningful pathways. We performed a simulation study, where genotypes were randomly drawn including homozygous reference, heterozygous and homozygous variant for each SNP Si = 1, 50 where the MAF of SNP is chosen uniformly at random. Of great interest was a pair consisting of rs1737501 CD247 and rs1495963 IL12RB2 both in heterozygous variant, involving operator AND at p<1×10–23. It was reported with occurrence of 12.2% in patients and 0.005% in controls giving a specificity score of 99.995%. In addition to the described pair, SNP in strong LD within CD247 (rs1737502) was scored again together with rs1495963. Functionally, both genes are involved in regulation response. Another pair rs16908086 and rs1773557 that pointed together to CD247 and MRVI2 created a pair with occurrence 21% versus and 3% in controls. In sum, our study constituted the first network analyses of predisposing factors and complex genetic traits enriched in informative loci in immunoregulatory genes. Rare polymorphic variants of these genes may constitute risk factors for development of AA. Disclosures No relevant conflicts of interest to declare.

Identification of Genetic Polymorphisms Contributing to Risk in MDS Using Innovative GWAS Approaches.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 734-734
Author(s):  
Sandra P Smieszek ◽  
Bartlomiej P Przychodzen ◽  
Ron Paquette ◽  
Rainer Richter ◽  
Manuel Afable ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Snp Array ◽  
Genetic Traits ◽  
Synonymous Snps ◽  
Homozygous Variant ◽  
Network Analyses

Abstract Abstract 734 Genetic predisposition to MDS and AML is likely polygenic and may involve several low penetrance alleles which in concert with exogenous factors result in highly variable phenotype and late presentation, not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies utilizing various SNP array (SNP-A) platforms, large scale investigations in various disorders have been conducted. A systems level understanding of particular disease allows for identification of candidate genetic variants as prognostic or diagnostic markers. We have applied 6.0 SNP-A containing 924.644 SNP probes to conduct a comprehensive genome-wide association study (GWAS) in MDS including sAML with the aim of identifying low prevalence genetic variants that contribute to individual disease risk. We have studied 189 patients with MDS and sAML and a cohort of 2230 controls. After exclusion of SNP's with call rate of <95% and those with violation of Hardy Weinberg equilibrium (p<.01), 809.802 SNPs (87.5% of initial set) were passed for further investigation. Single allele χ2 for all autosomal markers was performed. A set of 3600 SNP's pointing towards genes with minor allele frequency (MAF) <10% and p<.001 after Bonferroni correction (more conservative multiple hypothesis correction than False Discovery Rate) were selected. Out of 38 significant non-synonymous SNPs 3 were selected, while 3/64 exonic non synonymous SNPs were prioritized for final investigation. These included rs805267, rs2499953 and rs2681417 pointing towards LY6G5B with (OR 4.9), MMP26 (OR 4.7) and CD86 (OR2.9), respectively. LY6G5B gene was represented by marker rs4656334 (p<1×10–12) occurring at the heterozygous frequency of 16.3% vs. 5.4% in controls, and in homozygous frequency of 4.1% vs. 0.04% in controls resulting in MAF of 12.2% vs. 2.7% in controls (p<1×10-12). Rs2499953 and rs2499956 pointed towards MMP26 and was found in the heterozygous variant in 17.0% vs. 3.7% in controls. CD86 gene was represented by singular rs2681417 marker (p<1×10–7) occurring at the heterozygous frequency of 29.0% vs. 13.6% frequency in controls, and in homozygous frequency of 4.0% vs. 0.4% in controls. The 3/3536 strongest intronic SNPs included rs4656334, rs4647493 and rs700060 and directed via LD to informative genes ATF6 with odds 3.15, FANCC (OR 135.3) and RABGAP1 (OR 37.1) respectively. Of interest is that ATF6/αaRheb-mTOR signalling promotes survival of dormant tumour cells in vivo. ATF6 gene was represented by marker rs4656334 (p<1×10–7) and occurred at a heterozygous frequency of 7% vs. 8.3% in controls, while the homozygous constellation was 7 × higher in patients (14.6% vs. 2.4% in controls) with the corresponding MAF of 18.0 vs. 6.5%. Another 2 SNPs within this locus were highly significant (rs16860777, p<1×10–6; and rs12401299, p<1×10–6). Second potential locus identified in our study (FANCC gene) was represented by singular rs4647493 marker (p<1×10–20) occurring at the heterozygous frequency of 16.9% vs. 0.05% in controls. RABGAP1 gene was represented by singular rs700060 marker (p<1×10–17) occurring at the heterozygous frequency of 13.9% vs. allelic frequency of 0.3% in controls. While these results of analysis targeting individual SNP provide intriguing research avenues, such an approach offers only limited understanding of the complex genetic traits as not an individual SNP, but rather a joint action of several SNPs results in particular outcomes. Consequently, in study of MDS, we applied the network gene association analysis as a new paradigm incorporating both “operator OR” and “operator AND” thereby allowing for dependence and independence testing and possibly, to identification of meaningful pathways. We performed a simulation study, where genotypes were drawn including homozygous reference, heterozygous and homozygous variant for each SNP Si = 1,… 64 where the MAF of SNP is chosen uniformly at random. We have identified rs236113 and rs2499953 (MCM8 and MMP26), both in homozygous variant with occurrence of 19% in patients and 1.8% in controls at a specificity score 98.2% and p<1×10–32. Accordingly the presence of both SNP's increases relative risk given the specificity when both SNPs are present. In sum, our study constituted the first network analyses of predisposing factors taken in consideration as groups and identified informative loci that can lead to delineation of causative genetic profiles. Disclosures: No relevant conflicts of interest to declare.

Mass Screening for Non-Synonymous SNPs Using Custom Cancer Microarrays Directly Reveals Possible Pathogenic Predisposition Factors in AA

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1333-1333
Author(s):  
Bartlomiej P Przychodzen ◽  
Andres Jerez ◽  
Hideki Makishima ◽  
Kathryn M Guinta ◽  
Peter Chomczynski
Keyword(s):  
Immunosuppressive Therapy ◽  
Genetic Variants ◽  
Conflicts Of Interest ◽  
Immunosuppressive Treatment ◽  
Minor Allele ◽  
Healthy Population ◽  
Whole Genome ◽  
Synonymous Snps ◽  
Low Prevalence ◽  
The Impact

Abstract Abstract 1333 While immune mechanisms are involved in the pathogenesis of idiopathic aplastic anemia (AA), identification of heritable predisposition/susceptibility traits has been difficult due to the impact of exogenous factors and the low prevalence of AA. The seemingly sporadic and likely complex and heterogeneous traits leading to AA are not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies such as single nucleotide polymorphism arrays (SNP-A), large scale investigations in various disorders have been conducted. A systems level understanding of a particular disease may allow for the identification of candidate genetic variants as prognostic and diagnostic biomarkers. Previous studies utilized arrays with mostly tagging SNPs and thereby the identification of causative polymorphisms was only indirectly possible through the narrowing of LD intervals. We have applied a custom cancer chip (Illumina) containing 211,155 SNP probes designed for non-synonymous SNPs, allowing for a more direct discovery of pathogenic genes with the aim of identifying low prevalence genetic variants that contribute to the development, risk and therapy responsiveness in idiopathic AA. Our study involved 116 cases used for discovery and 120 cases to be used for confirmatory studies, as well as a cohort of 1964 controls to improve the power of detection. After exclusion of SNPs with a GenTrain score of <0.65 and those in violation of Hardy Weinberg equilibrium, 202,905 SNPs (96.0% of the initial set) were passed for further investigation. Single allele 2 statistics for all autosomal markers were performed; 853 SNPs with p<1×10-7 were selected. Subsequently, all 853 SNPs were screened for functional prediction (transcription factor binding site, affecting splicing, detrimental non-synonymous variant of proteins such as cytokines or cytokine receptors). An initial group of SNPs was expanded by all the SNPs being in linkage disequilibrium (>0.8) to a total of 7445 loci. Remarkably, informative LD blocks were identified, represented by multiple markers pointing to the presence of informative polymorphisms in the corresponding regions. A total of 3 SNPs were prioritized for final investigation based on the frequency differential between patients/controls. Of great interest was rs2544773 located in MYT1L represented directly by a singular marker. The frequency of the heterozygous variant among patients was 41.9% vs. 6.5% in controls and 15.0% vs. 0.4% for the minor homozygous variant (p<1×10–17). Our results suggest that carriers of at least one copy of the G allele (GA/AA) are at a higher risk of developing AA (OR 17.6). Another interesting variant identified was a non-synonymous SNP (rs13405539) located in DPYSL5 represented directly by a singular marker. This gene was recently associated with autoimmune myelopathy and cancer. Our analysis showed that minor allele has a protective potential and was present at a frequency in patients; occurring at a homozygous (AA) frequency of 1.8% vs. 16.4% in patients and controls, respectively and a heterozygous (GA) frequency of 14.6% vs. 49.2% in patients and controls respectively (p<1×10–20). Comparison of AA patients with healthy individuals has been a primary focus of GWAS. However, we have also compared subgroups defined by clinical criteria. We subdivided patients based on responsiveness to immunosuppressive therapy. CEBPZ was represented by rs3213746 through LD with rs12469082 (p<.0001). The heterozygous (CT) frequency observed amongst refractory patients was 12.4% vs. 1.4% and 8.2% vs. 0% for the minor homozygous (TT) variant, in refractory and responder, respectively. Odds ratio: Patients carrying at least one copy of the minor allele (CT/TT) are at much higher risk being a non-responder to immunosuppressive treatment (OR=26.3). Genotypic frequencies of patients that responded to immunosuppressive treatment were similar to the frequencies observed in healthy population. CEBPZ belongs to a family of CCAAT/enhancer proteins. It has been shown to interact with TP53 and therefore may play role in modulation of apoptosis. In sum, our study represents novel, whole genome approach using custom designed, high density cancer microarray that unravels new gene targets responsible for disease susceptibility as well as response to immunosuppressive therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response

2020 ◽  
Vol 21 (14) ◽  
pp. 4911 ◽  
Author(s):  
Dmitry S. Mikhaylenko ◽  
Marina V. Nemtsova ◽  
Irina V. Bure ◽  
Ekaterina B. Kuznetsova ◽  
Ekaterina A. Alekseeva ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Candidate Gene ◽  
Genetic Variants ◽  
Disease Risk ◽  
Significant Proportion ◽  
Therapy Response ◽  
Risk Groups ◽  
Antirheumatic Therapy ◽  
Disease Case ◽  
The Impact

Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide. Possible manifestations of RA can be represented by a wide variability of symptoms, clinical forms, and course options. This multifactorial disease is triggered by a genetic predisposition and environmental factors. Both clinical and genealogical studies have demonstrated disease case accumulation in families. Revealing the impact of candidate gene missense variants on the disease course elucidates understanding of RA molecular pathogenesis. A multivariate genomewide association study (GWAS) based analysis identified the genes and signalling pathways involved in the pathogenesis of the disease. However, these identified RA candidate gene variants only explain 30% of familial disease cases. The genetic causes for a significant proportion of familial RA have not been determined until now. Therefore, it is important to identify RA risk groups in different populations, as well as the possible prognostic value of some genetic variants for disease development, progression, and treatment. Our review has two purposes. First, to summarise the data on RA candidate genes and the increased disease risk associated with these alleles in various populations. Second, to describe how the genetic variants can be used in the selection of drugs for the treatment of RA.

Private or Public Law Enforcement? The Case of Digital Anti-Piracy Policies with Illegal Non-Monitored Behaviors

2016 ◽  
Vol 15 (4) ◽  
Author(s):  
Eric Darmon ◽  
Thomas Le Texier
Keyword(s):  
Large Scale ◽  
Conflicts Of Interest ◽  
Public Law ◽  
Social Planner ◽  
Private Enforcement ◽  
Digital Piracy ◽  
Public And Private ◽  
The Social ◽  
Public And Private Enforcement ◽  
The Impact

AbstractShould rights be publicly or privately enforced in the case of digital piracy? The emergence of large-scale anti-piracy laws and the existence of illegal non-monitored channels raise important issues for the design of anti-piracy policies. We study the impact of these demand-side policies in two enforcement settings (namely, public and private enforcement settings) with an outside adoption option for users of an illegal non-monitored channel. Our results show that public enforcement generates higher monitoring and lower price levels, and also higher legal welfare than private enforcement. However, we identify potential conflicts of interest between the legal seller and the social planner when the efficiency of the illegal non-monitored channel is low. Introducing supply-side policies, i.e. policies targeted to suppliers of illegal content, we find that they may have unexpected impacts and can damage legal welfare. We also identify situations in which the two policies are substitutes or complements.

P3399Influence of TCF21 rs12190287 in the coronary artery disease risk prediction. An association study in a Portuguese population

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Sousa ◽  
M Mendonca ◽  
A Pereira ◽  
F Mendonca ◽  
J Monteiro ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Disease Risk ◽  
Smoking Status ◽  
Genetic Risk Score ◽  
Strong Association ◽  
Portuguese Population ◽  
The Impact ◽  
Cad Risk

Abstract TCF21 is a member of the basic-helix-loop-helix (bHLH) transcriptor factor family, being critical for embryogenesis of the heart, kidney and spleen. TCF21 also regulates epicardium-derived cells differentiation into smooth muscle and fibroblast lineages. Aim Investigate the impact of TCF21 rs12190287 in the prediction and discrimination of CAD risk, individually or into a genetic risk score (GRS) formed by a set of 13 genetic variants. Methods We performed a case-control study with 3050 subjects (1619 coronary patients with 53.3±8 years; 78.9% male and 1431 controls with 52.8±8 years; 76.6% male) from GENEMACOR study. We investigated all traditional risk factors (TRF), as well as 13 genetic variants from GWAS with unknown pathophysiological pathway so far, including TCF21 (rs12190287), ZC3HC1 (rs11556924), PSRC1/SORTI (rs599839), PHACTR1 (rs1332844), MIA3 (rs17465637), SMAD3 (rs17228212), ZNF259 (rs964184), ADAMTS7 (rs3825807), CDKN2B (rs4977574), 9p21.3 (rs1333049), KIF6 (rs20455), PCSK9 (rs2114580) and GJA4 (rs618675). A multiplicative genetic risk score with these 13 genetic variants (m13GRS), was calculated. Subsequently, two logistic regressions were performed; primarily with all the TRF and all the genes individually and the second with TRF and m13GRS. Results The first multivariate analysis shows that, besides the strong association of the TRF with CAD risk (with smoking status on the top of the list, with an OR of 3.2; p<0.0001), TCF21 rs12190287 was the most significant variant from all the studied genetic set with a CAD risk of 1.5 (95% CI: 1.1–1.9; p=0.004), followed by the well-known genetic determinant CDKN2B rs4977574 (OR=1.4; 95% CI: 1.1–1.7; p<0.002) and ZC3HC1 rs11556924 (OR=1.3; 95% CI: 1.0–1.7; p=0.034). When GRS is included to the model, all the TRF remain in the equation by the same order, and the m13GRS persisted as an independent predictor for CAD risk (OR=1.7; 95% CI: 1.4–2.0; p<0.0001). Conclusion TCF21 rs12190287 is a risk factor for CAD in the Portuguese population, either individually or incorporated in a m13GRS. TCF21 risk is independent from TRF. In the future, TCF21 can provide a new clues to identify patients at high cardiovascular risk and become a potential target for gene therapy.

Reconstruction of GRACE Total Water Storage Through Automated Machine Learning

2020 ◽  
Author(s):  
Alex Sun ◽  
Bridget Scanlon ◽  
Himanshu Save ◽  
Ashraf Rateb
Keyword(s):  
Machine Learning ◽  
Spatial Variability ◽  
Large Scale ◽  
Water Storage ◽  
Total Water ◽  
New Paradigm ◽  
Satellite Mission ◽  
Automated Machine Learning ◽  
The Mean ◽  
The Impact

&lt;p&gt;The GRACE satellite mission and its follow-on, GRACE-FO, have provided unprecedented opportunities to quantify the impact of climate extremes and human activities on total water storage at large scales. The approximately one-year data gap between the two GRACE missions needs to be filled to maintain data continuity and maximize mission benefits. There is strong interest in using machine learning (ML) algorithms to reconstruct GRACE-like data to fill this gap. So far, most studies attempted to train and select a single ML algorithm to work for global basins. However, hydrometeorological predictors may exhibit strong spatial variability which, in turn, may affect the performance of ML models. Existing studies have already shown that no single algorithm consistently outperformed others over all global basins. In this study, we applied an automated machine learning (AutoML) workflow to perform GRACE data reconstruction. AutoML represents a new paradigm for optimal model structure selection, hyperparameter tuning, and model ensemble stacking, addressing some of the most challenging issues related to ML applications. We demonstrated the AutoML workflow over the conterminous U.S. (CONUS) using six types of ML algorithms and multiple groups of meteorological and climatic variables as predictors. Results indicate that the AutoML-assisted gap filling achieved satisfactory performance over the CONUS. For the testing period (2014/06&amp;#8211;2017/06), the mean gridwise Nash-Sutcliffe efficiency is around 0.85, the mean correlation coefficient is around 0.95, and the mean normalized root-mean square error is about 0.09. Trained models maintain good performance when extrapolating to the mission gap and to GRACE-FO periods (after 2017/06). Results further suggest that no single algorithm provides the best predictive performance over the entire CONUS, stressing the importance of using an end-to-end workflow to train, optimize, and combine multiple machine learning models to deliver robust performance, especially when building large-scale hydrological prediction systems and when predictor importance exhibits strong spatial variability.&lt;/p&gt;

Impact Of Total Nucleated Cell and CD34+ Cell Dose On Transplant Related Outcomes In Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplants

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2048-2048 ◽  
Author(s):  
Paul Martin ◽  
Shuli Li ◽  
Edwin P. Alyea ◽  
Vincent T. Ho ◽  
Corey S. Cutler ◽  
...  
Keyword(s):  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Reduced Intensity Conditioning ◽  
Allogeneic Hct ◽  
Cell Dose ◽  
The Impact ◽  
Reduced Intensity

Abstract Background Mobilized peripheral blood (PB) is the most common graft source for allogeneic hematopoietic transplantation (HCT) following reduced intensity conditioning (RIC). The impact, if any, of donor PB graft composition on major transplant outcomes in the RIC allogeneic HCT setting remains incompletely understood. Existing studies have focused primarily on CD34+ cell dose and report conflicting results, especially in relation to survival. The impact of total nucleated cell (TNC) dose has been less frequently evaluated, but limited studies with relatively small cohort sizes have reported higher TNC dose to be associated with improved survival. Methods In order to further explore the relationship between PB donor CD34+ cell dose, TNC dose and RIC HCT outcomes, we assessed 705 adult patients with hematological malignancies who underwent RIC allogeneic HCT at Dana Farber Cancer Institute/ Brigham and Women's Hospital (DFCI/BWH) between 2000 and 2010. The vast majority received a RIC regimen of fludarabine and busulfan (n=698). GVHD prophylaxis was tacrolimus based with or without sirolimus (524 vs. 171, respectively). Recipients of in vivo T-cell depletion (TCD) with antithymocyte globulin or ex-vivo TCD were excluded. The median age was 57 years (range,18-74). Patient's disease risk index (DRI) was categorized as low (n=164), intermediate (n=350), high (n=170) or very high (n=21) per Armand, et al (Blood, 2012). Transplants were categorized as matched (MRD n=273, MUD n=374) or mismatched (MMRD n=4, MMUD n=58). Results There was weak correlation between CD34+ cell dose and TNC (Spearman coefficient 0.25 [0.18-0.32]), and between CD34+/kg and TNC/kg with coefficient 0.25 [0.26, 0.39]. Cell doses for TNC effects were evaluated by quartiles. On multivariable analysis including age, DRI, donor source, gender, and CMV serostatus, higher TNC dose (top quartile, ≥10.8 x 10^10 cells) was independently associated with increased chronic GVHD (HR 1.33 [1.06-1.67], p=0.015) as well as decreased relapse (HR 0.74 [0.58-0.94], p=0.015). There was no effect on acute GVHD, engraftment, or non-relapse mortality. Importantly, higher TNC dose was associated with improved overall survival (HR 0.74 [0.59-0.94], p=0.014, Figure 1) and progression free survival, PFS (HR 0.76 [0.61-0.94], p=0.014). In contrast, although higher doses of CD34+ cells (> 10 x 10^6/kg vs. < 5 x10^6/kg) resulted in faster engraftment for both platelets and neutrophils (data not shown) and a decrease in non-relapse mortality ( HR 0.53 [0.30-0.93], p=0.027), there was no significant effect on acute or chronic GVHD incidence, relapse, PFS or survival. Conclusions These data suggest TNC dose is an important prognostic variable in T-replete RIC HCT with significant impact on survival and should, like CD34+ cell dose, be taken into consideration when planning donor graft infusions. Further studies are needed to confirm these data, and characterize the components of the PB graft that influence survival. Disclosures: No relevant conflicts of interest to declare.

Impact of Cytopenia Following Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Using Post-Transplant Cyclophoshamide

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2281-2281
Author(s):  
Villetard Ferdinand ◽  
Stefania Bramanti ◽  
Samia Harbi ◽  
Sabine Fürst ◽  
Catherine Faucher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Transplantation ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Conditioning Regimen ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Cell Dose ◽  
The Impact

Abstract Introduction Allogeneic transplantation from a haploidentical donor (HaploSCT) is an alternative strategy in the treatment of hematologic malignancies in absence of HLA-identical donor. Recent studies reported similar outcome after HaploSCT compared to HLA-identical transplantation in different settings (Bashey, JCO 2013; Wang, Blood 2015; Gosh, JCO 2016). Although survivals seemed promising after HaploSCT, hematopoietic recovery following such a mismatched transplantation could represent a limitation. Thus, our series aims to evaluate hematological recovery after HaploSCT using a post transplantation cyclophosphamide (PT-Cy) platform. Methods This retrospective monocentric study included consecutive patients with following criteria: adults with hematological malignancies; bone marrow or peripheral blood T-replete HaploSCT from 2011 to 2015; non-myeloablative (Baltimore approach) or reduced intensity conditioning (busulfan-based) regimen; PT-Cy as part of GVHD prophylaxis. Patients with primary graft failure were excluded. Absolute neutrophil count (ANC), red cells (RCT) or platelet transfusion (PT) requirements on day 30 (D30) and day 100 (D100) were analyzed among disease-free patients. We first separately evaluated the rate of patients with significant cytopenia in each lineage (defined by ANC < 1 G/L, RCT need, PT need) and searched for impact of pre-transplantation factors on cytopenia (multivariate analyses by binary logistic regression). Then, we evaluated outcome by D30- and D100-landmark analyses according to cytopenia. Results One hundred and forty six patients with a median age of 56 years (range: 19-73) were analyzed: 142 and 117 were evaluable at D30 (4 early deaths) and D100 (17 deaths, 11 relapses), respectively. At D30, 20% of patients had ANC<1G/L, 67% needed RCT and 63% needed PT. Corresponding values at D100 were 20%, 42% and 28%, respectively (Figure 1). At D30: the use of PBSC (HR 9.5, p=0.002) was significantly associated with ANC>1G/L at D30; the use of NMAC Baltimore schema (HR 0.3, p=0.012) and CD34+ cell dose > median (HR 0.4, p=0.041) decreased PT needs while hematopoietic cell transplantation comorbidity index (HCT-CI)≥3 (HR 3.3, p=0.004) was associated with PT needs; no factor was found to significantly influence RCT. At D100: Age>60 years (HR 2.4, p=0.045), female to male HaploSCT (HR 3.3, p=0.020) and HCT-CI≥3 (HR 3.7, p=0.006) were significantly associated with higher risk of RCT need; female to male HaploSCT (HR 3.6, p=0.015) and HCT-CI≥3 (HR 6.9, p=0.001) were associated with PT needs; no factor was found to significantly influence ANC. With a median follow up of 25 months (range: 5-55), cox multivariate model with adjustment by age (continuous), disease risk index (low/intermediate vs high/very high), HCT-CI (0-2 vs ≥3), conditioning regimen (baltimore vs. busulfan-based) and graft source (bone marrow vs PBSC) showed that ANC<1 G/L was strongly associated with higher NRM (HR 2.9, p=0.011) and shorter OS (HR 3.4, p<0.001), overcoming the impact of RCT and PT needs (Figure 2A and 2B). In contrast, D100 analysis showed that PT need was the most determinant factor of increased NRM (HR 13.7, p=0.013) and poor OS (HR 7.3, p=0.003), while both D100 ANC and RCT needs did not impact outcome (Figure 2C and 2D). Discussion We found that cytopenia remain a concern after HaploSCT, leading to increased NRM and OS. The absence of ANC>1G/L at D30 as well as the need of PT at D100 may be considered as a strong post transplantation factor predicting poor outcome. Some pre-transplantation factors of cytopenia have been identified, such as CD34+ cell dose, sex mismatch and graft source. Among them, some may help for donor selection while the optimal donor for HaploSCT is still unknown. Moreover, better neutrophil recovery at D30 is achieved with the use of PBSC. CD34+ optimal cell dose in this setting remains also to be determined. In addition, post transplantation events such GVHD and/or infections should be evaluate to explore their interactions with such cytopenia, aiming to develop early therapeutic interventions. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Time and well¬being

2015 ◽  
pp. 1-16
Author(s):  
Robert Levine
Keyword(s):  
Time Use ◽  
Large Scale ◽  
Public Policies ◽  
Well Being ◽  
Temporal Orientation ◽  
New Paradigm ◽  
Event Time ◽  
Country Level ◽  
The Impact ◽  
The Way

This paper examines the impact of temporal experience—time use, conceptions of time and temporal norms—on happiness and well-being and suggests public policies to enhance these experiences. First, it reviews literature concerning the interrelationships of time, money and happiness. Second, it reviews data and issues concerning the use of work and non-work hours around the world. Third, it describes a broader range of temporal issues to be considered in policymaking decisions, e.g. clock versus event time-keeping, monochronic versus polychronic approaches, the definition of wasted time, the pace of life, and temporal orientation. Finally, suggestions are of ered for the formulation of time-use policies intended to increase individual and collective happiness. It is a virtual truism that the way we use our time is the way we live our lives. Our time is our most valuable possession. Much of this time, however, is controlled by others, ranging from our employers to our closest family members. It is also clear that there are profound dif erences-- individual, socio-economic, cultural and national--in the degree to which people hold control over their own time (e.g., LEVINE, 1997; LEE, et al., 2007). It may be argued that public policies are needed to protect the “temporal rights” of individuals, particularly those who are most vulnerable to exploitation. This paper was sparked by an ambitious large-scale project in which I had the opportunity to participate. The project was initiated in the Spring of 2012 following a United Nations resolution, adopted unanimously by the General Assembly, placing “happiness” on the global agenda. The nation of Bhutan was asked to convene an interdisciplinary group of international “experts” to craft recommendations for policies to raise worldwide happiness; more specifically, to develop a “new paradigm for world development.” Bhutan, a small, landlocked, relatively poor Himalayan nation, was chosen for this task because of its pioneering Gross National Happiness (GNH) project. “Progress,” the GNH designers declared, “should be viewed not only through the lens of economics but also from spiritual, social, cultural and ecological perspectives.” Happiness and development, in other words, depend on more than growth and the accumulation of money. England, Canada and other countries and country-level organizations have subsequently followed Bhutan’s lead and established GNH measures of their own (LEVINE, 2013). One of the nine core domains of Bhutan’s GNH index is “time use,” which comprised my section of the report. The present paper draws heavily on that report and the insights that research of ered me. I will address four major sets of issues: I. The inter-relationships of time, money and happiness. Most importantly, what is the relevance of time use to well-being and happiness? II. Time Use: Work hour issues and policies. III. Other temporal factors that need to be considered when formulating policies to increase happiness. IV. Suggestions for policymaking: The call for a “Temporal Bill of Rights.”

scholarly journals The Oft-Overlooked Massively Parallel Reporter Assay: Where, When, and Which Psychiatric Genetic Variants are Functional?

2020 ◽  
Author(s):  
Bernard Mulvey ◽  
Tomas Lagunas ◽  
Joseph D. Dougherty
Keyword(s):  
Effect Size ◽  
Genetic Variants ◽  
Large Scale ◽  
De Novo ◽  
Disease Risk ◽  
Massively Parallel ◽  
Single Experiment ◽  
Biological Variables ◽  
Small Effect Size ◽  
Specific Implementation

AbstractNeuropsychiatric phenotypes have been long known to be influenced by heritable risk factors. The past decade of genetic studies have confirmed this directly, revealing specific common and rare genetic variants enriched in disease cohorts. However, the early hope for these studies—that only a small set of genes would be responsible for a given disorder—proved false. The picture that has emerged is far more complex: a given disorder may be influenced by myriad coding and noncoding variants of small effect size, and/or by rare but severe variants of large effect size, many de novo. Noncoding genomic sequences harbor a large portion of these variants, the molecular functions of which cannot usually be inferred from sequence alone. This creates a substantial barrier to understanding the higher-order molecular and biological systems underlying disease risk. Fortunately, a proliferation of genetic technologies—namely, scalable oligonucleotide synthesis, high-throughput RNA sequencing, CRISPR, and CRISPR derivatives—have opened novel avenues to experimentally identify biologically significant variants en masse. These advances have yielded an especially versatile technique adaptable to large-scale functional assays of variation in both untranscribed and untranslated regulatory features: Massively Parallel Reporter Assays (MPRAs). MPRAs are powerful molecular genetic tools that can be used to screen tens of thousands of predefined sequences for functional effects in a single experiment. This approach has several ideal features for psychiatric genetics, but remains underutilized in the field to date. To emphasize the opportunities MPRA holds for dissecting psychiatric polygenicity, we review here its applications in the literature, discuss its ability to test several biological variables implicated in psychiatric disorders, illustrate this flexibility with a proof-of-principle, in vivo cell-type specific implementation of the assay, and envision future outcomes of applying MPRA to both computational and experimental neurogenetics.

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