The Experts below are selected from a list of 249 Experts worldwide ranked by ideXlab platform
Elizabeth Rose Mayeda - One of the best experts on this subject based on the ideXlab platform.
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evaluation of Selective Survival and sex gender differences in dementia incidence using a simulation model
JAMA Network Open, 2021Co-Authors: Crystal Shaw, Eleanor Hayeslarson, Maria M Glymour, Lindsay C Kobayashi, Carole Dufouil, Timothy J. Hohman, Rachel A. Whitmer, Ron Brookmeyer, Elizabeth Rose MayedaAbstract:Importance Dementia research is susceptible to bias arising from Selective Survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer Survival also influence dementia incidence. Objective To assess the role of Selective Survival in explaining reported sex/gender differences in dementia incidence. Design, Setting, and Participants This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective Survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020. Exposure Sex/gender, conceptualized as the combination of biological sex and social consequences of gender. Main Outcomes and Measures Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to Selective Survival. Results At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of Selective Survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women). Conclusions and Relevance These results suggest that Selective Survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for Selective Survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.
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the competing risk of death and Selective Survival cannot fully explain the inverse cancer dementia association
Alzheimers & Dementia, 2020Co-Authors: Eleanor Hayeslarson, Sarah F Ackley, Scott C Zimmerman, Monica Ospinaromero, Maria M Glymour, Rebecca E Graff, John S Witte, Lindsay C Kobayashi, Elizabeth Rose MayedaAbstract:INTRODUCTION We evaluated whether competing risk of death or Selective Survival could explain the reported inverse association between cancer history and dementia incidence (incidence rate ratio [IRR] ≈ 0.62-0.85). METHODS A multistate simulation model of a cancer- and dementia-free cohort of 65-year-olds was parameterized with real-world data (cancer and dementia incidence, mortality), assuming no effect of cancer on dementia (true IRR = 1.00). To introduce competing risk of death, cancer history increased mortality. To introduce Selective Survival, we included a factor (prevalence ranging from 10% to 50%) that reduced cancer mortality and dementia incidence (IRRs ranged from 0.30 to 0.90). We calculated IRRs for cancer history on dementia incidence in the simulated cohorts. RESULTS Competing risk of death yielded unbiased cancer-dementia IRRs. With Selective Survival, bias was small (IRRs = 0.89 to 0.99), even under extreme scenarios. DISCUSSION The bias induced by Selective Survival in simulations was too small to explain the observed inverse cancer-dementia link, suggesting other mechanisms drive this association.
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Does Selective Survival before study enrolment attenuate estimated effects of education on rate of cognitive decline in older adults? A simulation approach for quantifying Survival bias in life course epidemiology.
International journal of epidemiology, 2018Co-Authors: Elizabeth Rose Mayeda, Maria M Glymour, Teresa J. Filshtein, Yorghos Tripodis, Alden L. GrossAbstract:Background The relationship between education and late-life cognitive decline is controversial. Selective Survival between early life, when education is typically completed, and late life, when cognitive ageing studies take place, could attenuate effect estimates. Methods We quantified potential Survival bias (collider-stratification bias) in estimation of the effect of education on late-life cognitive decline by simulating hypothetical cohorts of 20-year-olds and applying cumulative mortality from US life tables. For each of four causal scenarios (2000 replications each), we compared the estimated versus causal effect of education on cognitive decline over 9 years, starting at age 60, 75 or 90 in random samples of n = 2000 people who survived to each age. Results Effects of education on cognitive decline were underestimated when both education and U, another determinant of cognitive decline, influenced mortality (collider-stratification bias). The magnitude of bias was sensitive to the magnitude of the effect of U on cognitive decline and whether there was a multiplicative interaction between education and U on mortality. For example, when there was a multiplicative interaction between education and U on mortality, 95% confidence interval coverage of the causal effect ranged from 83.4% to 50.4% at age 60 and 25.8% to 0.2% at age 90. Conclusions Selective Survival could lead to underestimation of effects of education on late-life cognitive decline. Our simulations map Survival bias to testable assumptions about underlying causal structures.
Sankar Ghosh - One of the best experts on this subject based on the ideXlab platform.
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nf κb activation by the pre t cell receptor serves as a Selective Survival signal in t lymphocyte development
Immunity, 2000Co-Authors: Reinhard E Voll, Eijiro Jimi, Roderick J Phillips, Domingo F Barber, Mercedes Rincon, Adrian Hayday, Richard A Flavell, Sankar GhoshAbstract:Abstract Activation of the transcription factor NF-κB and pre-T cell receptor (pre-TCR) expression is tightly correlated during thymocyte development. Inhibition of NF-κB in isolated thymocytes in vitro results in spontaneous apoptosis of cells expressing the pre-TCR, whereas inhibition of NF-κB in transgenic mice through expression of a mutated, superrepressor form of IκBα leads to a loss of β-selected thymocytes. In contrast, the forced activation of NF-κB through expression of a dominant-active IκB kinase allows differentiation to proceed to the CD4 + CD8 + stage in a Rag1 −/− mouse that cannot assemble the pre-TCR. Therefore, signals emanating from the pre-TCR are mediated at least in part by NF-κB, which provides a Selective Survival signal for developing thymocytes with productive β chain rearrangements.
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nf κb activation by the pre t cell receptor serves as a Selective Survival signal in t lymphocyte development
Immunity, 2000Co-Authors: Reinhard E Voll, Eijiro Jimi, Roderick J Phillips, Domingo F Barber, Mercedes Rincon, Adrian Hayday, Richard A Flavell, Sankar GhoshAbstract:Activation of the transcription factor NF-kappa B and pre-T cell receptor (pre-TCR) expression is tightly correlated during thymocyte development. Inhibition of NF-kappa B in isolated thymocytes in vitro results in spontaneous apoptosis of cells expressing the pre-TCR, whereas inhibition of NF-kappa B in transgenic mice through expression of a mutated, superrepressor form of I kappa B alpha leads to a loss of beta-selected thymocytes. In contrast, the forced activation of NF-kappa B through expression of a dominant-active I kappa B kinase allows differentiation to proceed to the CD4(+)CD8(+) stage in a Rag1(-/-) mouse that cannot assemble the pre-TCR. Therefore, signals emanating from the pre-TCR are mediated at least in part by NF-kappa B, which provides a Selective Survival signal for developing thymocytes with productive beta chain rearrangements.
Maria M Glymour - One of the best experts on this subject based on the ideXlab platform.
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evaluation of Selective Survival and sex gender differences in dementia incidence using a simulation model
JAMA Network Open, 2021Co-Authors: Crystal Shaw, Eleanor Hayeslarson, Maria M Glymour, Lindsay C Kobayashi, Carole Dufouil, Timothy J. Hohman, Rachel A. Whitmer, Ron Brookmeyer, Elizabeth Rose MayedaAbstract:Importance Dementia research is susceptible to bias arising from Selective Survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer Survival also influence dementia incidence. Objective To assess the role of Selective Survival in explaining reported sex/gender differences in dementia incidence. Design, Setting, and Participants This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective Survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020. Exposure Sex/gender, conceptualized as the combination of biological sex and social consequences of gender. Main Outcomes and Measures Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to Selective Survival. Results At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of Selective Survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women). Conclusions and Relevance These results suggest that Selective Survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for Selective Survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.
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the competing risk of death and Selective Survival cannot fully explain the inverse cancer dementia association
Alzheimers & Dementia, 2020Co-Authors: Eleanor Hayeslarson, Sarah F Ackley, Scott C Zimmerman, Monica Ospinaromero, Maria M Glymour, Rebecca E Graff, John S Witte, Lindsay C Kobayashi, Elizabeth Rose MayedaAbstract:INTRODUCTION We evaluated whether competing risk of death or Selective Survival could explain the reported inverse association between cancer history and dementia incidence (incidence rate ratio [IRR] ≈ 0.62-0.85). METHODS A multistate simulation model of a cancer- and dementia-free cohort of 65-year-olds was parameterized with real-world data (cancer and dementia incidence, mortality), assuming no effect of cancer on dementia (true IRR = 1.00). To introduce competing risk of death, cancer history increased mortality. To introduce Selective Survival, we included a factor (prevalence ranging from 10% to 50%) that reduced cancer mortality and dementia incidence (IRRs ranged from 0.30 to 0.90). We calculated IRRs for cancer history on dementia incidence in the simulated cohorts. RESULTS Competing risk of death yielded unbiased cancer-dementia IRRs. With Selective Survival, bias was small (IRRs = 0.89 to 0.99), even under extreme scenarios. DISCUSSION The bias induced by Selective Survival in simulations was too small to explain the observed inverse cancer-dementia link, suggesting other mechanisms drive this association.
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Does Selective Survival before study enrolment attenuate estimated effects of education on rate of cognitive decline in older adults? A simulation approach for quantifying Survival bias in life course epidemiology.
International journal of epidemiology, 2018Co-Authors: Elizabeth Rose Mayeda, Maria M Glymour, Teresa J. Filshtein, Yorghos Tripodis, Alden L. GrossAbstract:Background The relationship between education and late-life cognitive decline is controversial. Selective Survival between early life, when education is typically completed, and late life, when cognitive ageing studies take place, could attenuate effect estimates. Methods We quantified potential Survival bias (collider-stratification bias) in estimation of the effect of education on late-life cognitive decline by simulating hypothetical cohorts of 20-year-olds and applying cumulative mortality from US life tables. For each of four causal scenarios (2000 replications each), we compared the estimated versus causal effect of education on cognitive decline over 9 years, starting at age 60, 75 or 90 in random samples of n = 2000 people who survived to each age. Results Effects of education on cognitive decline were underestimated when both education and U, another determinant of cognitive decline, influenced mortality (collider-stratification bias). The magnitude of bias was sensitive to the magnitude of the effect of U on cognitive decline and whether there was a multiplicative interaction between education and U on mortality. For example, when there was a multiplicative interaction between education and U on mortality, 95% confidence interval coverage of the causal effect ranged from 83.4% to 50.4% at age 60 and 25.8% to 0.2% at age 90. Conclusions Selective Survival could lead to underestimation of effects of education on late-life cognitive decline. Our simulations map Survival bias to testable assumptions about underlying causal structures.
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stroke disparities in older americans is wealth a more powerful indicator of risk than income and education
Stroke, 2008Co-Authors: Mauricio Avendano, Maria M GlymourAbstract:BACKGROUND AND PURPOSE-: This study examines the independent effect of wealth, income, and education on stroke and how these disparities evolve throughout middle and old age in a representative cohort of older Americans. METHODS-: Stroke-free participants in the Health and Retirement Study (n=19 565) were followed for an average of 8.5 years. Total wealth, income, and education assessed at baseline were used in Cox proportional hazards models to predict time to stroke. Separate models were estimated for 3 age-strata (50 to 64, 65 to 74, and ≥75), and incorporating risk factor measures (smoking, physical activity, body mass index, hypertension, diabetes, and heart disease). RESULTS-: 1542 subjects developed incident stroke. Higher education predicted reduced stroke risk at ages 50 to 64, but not after adjustment for wealth and income. Wealth and income were independent risk factors for stroke at ages 50 to 64. Adjusted hazard ratios comparing the lowest decile with the 75th-90th percentiles were 2.3 (95% CI 1.6, 3.4) for wealth and 1.8 (95% CI 1.3, 2.6) for income. Risk factor adjustment attenuated these effects by 30% to 50%, but coefficients for both wealth (HR=1.7, 95% CI 1.2, 2.5) and income (HR=1.6, 95% CI 1.2, 2.3) remained significant. Wealth, income, and education did not consistently predict stroke beyond age 65. CONCLUSIONS-: Wealth and income are independent predictors of stroke at ages 50 to 64 but do not predict stroke among the elderly. This age patterning might reflect buffering of the negative effect of low socioeconomic status by improved access to social and health care programs at old ages, but may also be an artifact of Selective Survival.
Joseph S Anderson - One of the best experts on this subject based on the ideXlab platform.
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generation of an hiv 1 resistant immune system with cd34 hematopoietic stem cells transduced with a triple combination anti hiv lentiviral vector
Journal of Virology, 2012Co-Authors: Jon Walker, Gerhard Bauer, Rachel X Chen, Jeannine Mcgee, Catherine Nacey, Richard B Pollard, Mehrdad Abedi, Jan A Nolta, Joseph S AndersonAbstract:HIV gene therapy has the potential to offer an alternative to the use of current small-molecule antiretroviral drugs as a treatment strategy for HIV-infected individuals. Therapies designed to administer HIV-resistant stem cells to an infected patient may also provide a functional cure, as observed in a bone marrow transplant performed with hematopoietic stem cells (HSCs) homozygous for the CCR5-Δ32-bp allele. In our current studies, preclinical evaluation of a combination anti-HIV lentiviral vector was performed, in vivo, in humanized NOD-RAG1(-/-) IL2rγ(-/-) knockout mice. This combination vector, which displays strong preintegration inhibition of HIV-1 infection in vitro, contains a human/rhesus macaque TRIM5α isoform, a CCR5 short hairpin RNA (shRNA), and a TAR decoy. Multilineage hematopoiesis from anti-HIV lentiviral vector-transduced human CD34(+) HSCs was observed in the peripheral blood and in various lymphoid organs, including the thymus, spleen, and bone marrow, of engrafted mice. Anti-HIV vector-transduced CD34(+) cells displayed normal development of immune cells, including T cells, B cells, and macrophages. The anti-HIV vector-transduced cells also displayed knockdown of cell surface CCR5 due to the expression of the CCR5 shRNA. After in vivo challenge with either an R5-tropic BaL-1 or X4-tropic NL4-3 strain of HIV-1, maintenance of human CD4(+) cell levels and a Selective Survival advantage of anti-HIV gene-modified cells were observed in engrafted mice. The data provided from our study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validates its potential application in future clinical trials.
Gerhard Bauer - One of the best experts on this subject based on the ideXlab platform.
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generation of an hiv 1 resistant immune system with cd34 hematopoietic stem cells transduced with a triple combination anti hiv lentiviral vector
Journal of Virology, 2012Co-Authors: Jon Walker, Gerhard Bauer, Rachel X Chen, Jeannine Mcgee, Catherine Nacey, Richard B Pollard, Mehrdad Abedi, Jan A Nolta, Joseph S AndersonAbstract:HIV gene therapy has the potential to offer an alternative to the use of current small-molecule antiretroviral drugs as a treatment strategy for HIV-infected individuals. Therapies designed to administer HIV-resistant stem cells to an infected patient may also provide a functional cure, as observed in a bone marrow transplant performed with hematopoietic stem cells (HSCs) homozygous for the CCR5-Δ32-bp allele. In our current studies, preclinical evaluation of a combination anti-HIV lentiviral vector was performed, in vivo, in humanized NOD-RAG1(-/-) IL2rγ(-/-) knockout mice. This combination vector, which displays strong preintegration inhibition of HIV-1 infection in vitro, contains a human/rhesus macaque TRIM5α isoform, a CCR5 short hairpin RNA (shRNA), and a TAR decoy. Multilineage hematopoiesis from anti-HIV lentiviral vector-transduced human CD34(+) HSCs was observed in the peripheral blood and in various lymphoid organs, including the thymus, spleen, and bone marrow, of engrafted mice. Anti-HIV vector-transduced CD34(+) cells displayed normal development of immune cells, including T cells, B cells, and macrophages. The anti-HIV vector-transduced cells also displayed knockdown of cell surface CCR5 due to the expression of the CCR5 shRNA. After in vivo challenge with either an R5-tropic BaL-1 or X4-tropic NL4-3 strain of HIV-1, maintenance of human CD4(+) cell levels and a Selective Survival advantage of anti-HIV gene-modified cells were observed in engrafted mice. The data provided from our study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validates its potential application in future clinical trials.
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Selective Survival of peripheral blood lymphocytes in children with hiv 1 following delivery of an anti hiv gene to bone marrow cd34 cells
Molecular Therapy, 2005Co-Authors: Greg M Podsakoff, Barbara C Engel, Denise A Carbonaro, Christopher S Choi, E M Smogorzewska, Gerhard Bauer, David Selander, Susan Csik, Kathy Wilson, Michael R BettsAbstract:Two HIV-1-infected children on antiretroviral therapy were enrolled into a clinical study of retroviral-mediated transfer of a gene that inhibits replication of HIV-1, targeting bone marrow CD34+ hematopoietic stem/progenitor cells. Two retroviral vectors were used, one encoding a "humanized" dominant-negative REV protein (huM10) that is a potent inhibitor of HIV-1 replication and one encoding a nontranslated marker gene (FX) to serve as an internal control for the level of gene marking. Peripheral blood mononuclear cells (PBMC) containing the huM10 gene or FX gene were detected by quantitative PCR at frequencies of approximately 1/10,000 in both subjects for the first 1-3 months following re-infusion of the gene-transduced bone marrow, but then were at or below the limits of detection (<1/1,000,000) at most times over 2 years. In one patient, a reappearance of PBMC containing the huM10 gene, but not the FX gene, occurred concomitant with a rise in the HIV-1 viral load during a period of nonadherence to the antiretroviral regimen. Unique clones of gene-marked PBMC were detected by LAM-PCR during the time of elevated HIV-1 levels. These findings indicate that there was a Selective Survival advantage for PBMC containing the huM10 gene during the time of increased HIV-1 load.