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Results for “Surrogate variables analysis”

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At least 19 recordsLinked to original sources

PubMed2026

DNA Methylation and Proteomic Profiling of Postmortem Brain Tissue Reveals Epigenetic Dysregulation and Neuroinflammatory in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS).

BACKGROUND: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by FMR1 premutation CGG repeat expansions (55-200 repeats). The epigenetic landscape of the FXTAS brain remains uncharacterized. We performed genome-wide DNA methylation profiling of postmortem prefrontal cortex tissue to identify differentially methylated positions (DMPs) and candidate genes, and sought protein-level support for a neuroinflammatory signal. METHODS: DNA methylation was profiled in postmortem prefrontal cortex (Brodmann area 9) from 27 male FXTAS cases and 29 male controls using the Illumina MethylationEPIC array (EPICv1 and EPICv2 platforms), merging 721,802 common probes. Surrogate variable analysis (SVA) controlled for confounders. DMPs were defined by |Δβ| > 0.10 and FDR < 0.05; exploratory Reactome 2024 pathway analysis was performed on the DMP-associated gene list. Targeted proteomic profiling was performed in the same brain region using the Olink (proximity extension assay) Inflammation panel in 9 FXTAS cases and 12 controls, with SVA-adjusted differential abundance analysis, and concordance assessment against a prior mass spectrometry dataset. RESULTS: We identified 108 significant cg-type DMPs mapping to 80 genes (50 hypermethylated, 58 hypomethylated in FXTAS). The strongest signal was CYP2E1 (7 concordant hypomethylated DMPs, mean Δβ = -0.143), an oxidative stress gene also implicated in Parkinson's disease. FTCD, a one-carbon cycle enzyme, carried 5 hypermethylated DMPs (mean Δβ = +0.210). A cluster of DMP-associated genes with established roles in innate immune and NF-κB signaling, TRAF3 (the single most significant DMP among the inflammation genes, hypermethylated), BATF, RCOR1, and MSI2; they pointed toward neuroinflammatory dysregulation. Additional genes included LINGO1 (myelination inhibitor), SYT3 (synaptic vesicle), and SLC39A4 (zinc transporter). Exploratory Reactome enrichment using the DMP-associated gene set nominated themes including neuroinflammation resolution, axonal growth inhibition, zinc homeostasis, and CYP2E1 metabolism at nominal significance (p<0.05); however, the gene-to-pathway mapping rate was low and no pathway survived correction for multiple testing. Olink proteomic analysis independently identified 60 significantly altered inflammation proteins (59 downregulated), including CXCL8, CXCL10, IL6, IL15, IL18, TLR3, IRAK1/4, and complement C1QA, which were directionally concordant with prior mass spectrometry data. CONCLUSIONS: This integrated study reveals a genome-wide epigenetic signature in the FXTAS prefrontal cortex implicating oxidative stress, myelination failure, zinc dysregulation, one-carbon cycle disruption, and most notably a coordinated set of epigenetically altered genes governing innate immune and NF-κB signaling. Convergence of TRAF3 hypermethylation with independent downregulation of TLR3 and NF-κB-pathway proteins at the protein level supports a coherent, cross-platform model of dysregulated neuroinflammatory signaling in FXTAS, identified here through individual gene- and protein-level convergence rather than formal pathway enrichment. FTCD hypermethylation proposes a self-reinforcing epigenetic loop via SAM depletion. These multi-omic findings establish FXTAS as a disorder of pervasive epigenetic reprogramming and nominate candidate genes for future mechanistic and therapeutic investigation.

CYP2E1↗

PubMed2025

Simultaneous inference for generalized linear models with unmeasured confounders.

Tens of thousands of simultaneous hypothesis tests are routinely performed in genomic studies to identify differentially expressed genes. However, due to unmeasured confounders, many standard statistical approaches may be substantially biased. This paper investigates the large-scale hypothesis testing problem for multivariate generalized linear models in the presence of confounding effects. Under arbitrary confounding mechanisms, we propose a unified statistical estimation and inference framework that harnesses orthogonal structures and integrates linear projections into three key stages. It begins by disentangling marginal and uncorrelated confounding effects to recover the latent coefficients. Subsequently, latent factors and primary effects are jointly estimated through lasso-type optimization. Finally, we incorporate projected and weighted bias-correction steps for hypothesis testing. Theoretically, we establish the identification conditions of various effects and non-asymptotic error bounds. We show effective Type-I error control of asymptotic-tests as sample and response sizes approach infinity. Numerical experiments demonstrate that the proposed method controls the false discovery rate by the Benjamini-Hochberg procedure and is more powerful than alternative methods. By comparing single-cell RNA-seq counts from two groups of samples, we demonstrate the suitability of adjusting confounding effects when significant covariates are absent from the model.

Hidden variables↗

PubMed1992

Influence of socioeconomic status on cardiovascular diseases in Hong Kong.

STUDY OBJECTIVE: The aim was to explore the relationships between five socioeconomic variables and three main cardiovascular diseases (ischaemic heart disease, hypertensive disease, and cerebrovascular disease) in Hong Kong. DESIGN: This cross sectional study used data from the 1986 by-census and registered death data for 1985 to 1987 in Hong Kong. For each of 24 districts, the correlation coefficients between log standardised mortality ratios for the three cardiovascular diseases and the percentages of professional and administrative workers, production and agricultural workers, persons aged 15 and over having tertiary education, households with higher income, and people living in private residential blocks were calculated. Besides simple linear regression and correlation, factor analysis was used to produce a new single surrogate measure summarising the five most useful variables in 24 sets of districts. SETTING: The whole Hong Kong area (population approximately 5.5 million) was divided into 24 districts, which were the study units. MEASUREMENTS AND MAIN RESULTS: For ischaemic heart disease in men, the correlation coefficients of the log standardised mortality ratios with the five socioeconomic variables as well as with the factor score were all statistically significant. For women, statistical significance was obtained in only two of five socioeconomic variables. No such trends were obtained for the other two cardiovascular diseases for either men or women. CONCLUSIONS: The study suggests that in Hong Kong in recent years, a higher level of socioeconomic status is associated with higher risk of death from ischaemic heart disease; but this association is not present for hypertensive disease and cerebrovascular disease.

Adolescent↗

PubMed1992

Logical and analytic issues in dental/oral product comparison research.

Possible meanings of "superiority" and "equivalence" in comparative dental studies are considered. A proposed refinement of vocabulary is introduced to precisely distinguish between these meanings. Implications for data analysis of different interpretations of "superiority" and "equivalence" are explored, as are implications for study design where design and analytic considerations are inseparable. Conceptual problems of equivalence studies are stressed. Choice of analytic unit(s), scaling of dependent variables, use of surrogate variables, and validity checking are discussed as they pertain to comparative studies. Analytic methods for correlated responses and categorized responses are briefly surveyed, particularly with reference to periodontal research.

Analysis of Variance↗

PubMed1986

Ethnic differences in Australian fertility.

Historically, immigration has played an important role in the demographic evolution of the modern Australian society. In order to measure the demographic impact of immigration, it is necessary to study the fertility behaviour of various immigrant groups in Australia. In this paper, ethnic differences in Australian fertility have been analysed, using country of birth as a surrogate variable for ethnicity. Main sources of data used are the population censuses and the birth registers. Most of the data presented refer to 1981, as analysis of data pertaining to 1971 and 1976 was reported in earlier papers. The study has shown that fertility of most of the European immigrants (except the Dutch and the Maltese), has been converging towards the Australian norm. The non-European immigrants have lower fertility, with the exception of the newly arrived refugee groups from Asia and the Middle East.

Adolescent↗

PubMed1990

The relationship of daily mortality to suspended particulates in Santa Clara County, 1980-1986.

This paper explores the relationship between daily mortality and suspended particulates in Santa Clara County, CA, for years 1980 to 1986. An association was found between high particulate concentrations and increased mortality. This association persists after adjustment for temperature, relative humidity, year, and seasonality. Contrary to expectation, the magnitude of the particulate effect appears the same or larger than that estimated for London, despite Santa Clara County's cleaner air. The persistence of an effect at these lower particulate concentrations suggests that the particulate variable may be acting as a surrogate for some constituent particles, such as acid aerosols.

Age Factors↗

PubMedDate not supplied

Uses of epidemiologic information in pollution episode management.

Epidemiologic information and analysis are essential for the process of health risk assessment and management in pollution episodes. Recognition of causal associations between exposure and disease requires an understanding of the nature of data upon which such associations are based and of the limitations that affect such data. Data concerned with disease detection are often affected by long and variable latencies, clinical nonspecificity, low frequencies (small population sizes), and reporting biases. Data concerned with measuring exposures must take into account pathway uncertainties, probable low dose levels, inability to develop dose-response information, and the frequent necessity to rely on indirect surrogates for dose estimation. Where such difficulties can be overcome, epidemiologic analysis can be decisive in identifying causal relationships. More often, data limitations require more limited conclusions. Case studies from New York, Michigan, South Carolina, and Massachusetts illustrate the impact of these principles on the process of health risk assessment.

Data Collection↗

PubMed1987

Lack of demonstrable density-dependent fecundity of schistosomiasis mansoni: analyses of Egyptian quantitative human autopsies.

Conflicting interpretations regarding the fecundity of schistosomes infecting human beings have arisen and are, in part, due to the inability to directly measure the parameters. The inability to experimentally manipulate human beings necessitates the use of surrogate variables, i.e., number of eggs per gram of feces, as an indicator of worm burden. This study reanalyzes data from quantitative autopsies performed in Egypt by Cheever and colleagues on individuals with active Schistosoma mansoni infections. Exploratory regression analysis of the relationship of female worms recovered to eggs/g of feces and of female worms to eggs retained in host tissues suggests a linear relationship in both cases. Over the observed range of female worms recovered from an individual human being, the estimated worm fecundity, as measured by the number of eggs either in feces or retained in tissues per female worm, is not significantly different from a constant value. Hence, density-dependent fecundity of S. mansoni in the human host, as suggested by others, is not demonstrated in these data.

Adolescent↗

PubMed1987

Hypertension and the genetics of red cell membrane abnormalities.

Hypertension represents the upper 15-25% of the blood pressure distribution in industrialized countries. The trait is practically absent in primitive societies and is made manifest by diet and lifestyles in industrialized countries. High blood pressure is an important risk factor for strokes, heart disease and renal disease. The frequency of hypertension is higher among blacks than among whites in the USA. Various twin, family and adoption studies indicate a strong genetic effect on blood pressure. The genetic mechanisms are unknown. Membrane transport variability has been studied in red cells as a surrogate for analogous alterations in smooth muscle or renal cells. Among the various transport systems, erythrocyte sodium-lithium countertransport (CT) has been consistently elevated in variable proportions of Caucasian hypertensives. Genetic studies of countertransport levels have shown familial aggregation and higher concordance for monozygotic than dizygotic twins. Complex segregation analysis suggests the action of a major gene superimposed on a polygenic background. The postulated gene (B) raises CT activity and has a population frequency of 0.25. CT levels of the common AA homozygotes and AB heterozygotes cannot be distinguished from each other, whereas CT activity of BB homozygotes (6% of the population) is significantly elevated. Although the CT gene contributes only 2.7% to 3.5% of the variability of blood pressure over its entire range, 14% to 20% of persons with systolic hypertension (greater than 140 mmHg) are BB homozygotes rather than the expected 6% to 7%. A much lower frequency of elevated countertransport activity among black hypertensives suggests genetic heterogeneity in the pathogenesis of high blood pressure. Further investigations on the mechanism and genetic linkage relationships of the putative CT gene may aid in elucidating an important mechanism of blood pressure elevation and will allow molecular approaches in the future.

Antiporters↗

PubMed1990

The effects of the new 65 mile-per-hour speed limit on rural highway fatalities: a state-by-state analysis.

This paper examines the effects of the new 65 mile-per-hour (mph) speed limit on U.S. rural highway fatality counts. Separate analyses are conducted for each of the 40 states that had adopted the new (higher) limit by mid-1988. Using monthly Fatal Accident Reporting System (FARS) data from January 1976 through November 1988, time-series regression equations--including policy variables, seasonal variables, and surrogate exposure variables--are estimated for each state. The results suggest that the new laws have increased fatalities on both rural interstate and rural noninterstate highways in most states, but also that these effects differ substantially across the states. For rural interstate fatalities the estimates suggest a median (among the 40 states) effect of the increased speed limit of roughly 15% more fatalities; the median estimates for rural noninterstates suggest a 5% increase in fatalities due to the increased speed limits. Estimates such as those reported here should be revised as more information becomes available.

Accidents, Traffic↗

PubMed1992

Determinants of lung cancer risk among cadmium-exposed workers.

Workers at a cadmium recovery plant in Globe, Colorado, showed an increased risk of lung cancer, which some investigators have attributed to cadmium exposure. We conducted a cohort mortality analysis of this work force and a case-control analysis of the lung cancer cases within this work force in order to assess the probable causes of the lung cancer excess. The Globe plant began as a lead smelter about 1886, switched to arsenic production in 1920, and became a cadmium metal production facility in 1926. Cadmium, arsenic, and cigarette smoking are three potential lung carcinogens found in this workplace. Industrial hygiene data collected from 1943 onward served as the basis for the National Institute for Occupational Safety and Health (NIOSH)-derived exposure algorithm that assigned cadmium exposure estimates to employees based on their work area in the plant and calendar time. Few exposure data existed for substances other than cadmium. Feedstock ore concentrations were used as a surrogate measure of air arsenic levels. The arsenic content of the fines used as feedstock prior to 1940 was considerably higher than that of the fines used after 1940. Smoking histories had been obtained previously for 45% of the workers. A case-control analysis of the 25 cases of lung cancer known to have occurred among these workers through 1982 was conducted using three controls per case, matched by closest data of hire and age at hire. Potential causal agents for lung cancer included cadmium exposure, cigarette smoking, and arsenic exposure. Exposure variables for each case and control included estimated cumulative cadmium exposure in milligram-years per cubic meter, cigarette smoking history, and plant arsenic exposure status at the time of hire. Estimated cumulative cadmium exposures of cases and controls did not differ overall or within the date-of-hire strata. Cases were more than eight times more likely to have been cigarette smokers than were controls. Lung cancer risk in this workplace was more closely related to the period of hire, not to the cumulative cadmium exposure. The period of hire appears to be a surrogate for arsenic exposure as related to feedstock. The measures used here seem to indicate that exposure to arsenic and cigarette particulates, rather than to cadmium particulates, may have caused the increased rate of lung cancer of these workers.

Adult↗

PubMed1991

Adjustment for non-differential misclassification error in the generalized linear model.

It is well known that estimates of association between an outcome variable and a set of categorical covariates, some of which are measured with misclassification, tend to be biased upon application of the usual methods of estimation that ignore the classification error. We propose a method to adjust for misclassification in covariates when one applies the generalized linear model. In the case where one can observe some true covariates only through surrogates, we combine a latent class analysis with the approach to incorporate multiple surrogates into the model. We include discussion on the efficacy of repeated measurements which one can view as a special case of multiple surrogates with identical distribution. We provide two examples to demonstrate the applicability of the method and the efficacy of multiple replicates for a covariate subject to misclassification in a regression framework.

Adolescent↗

PubMed1990

Do-not-resuscitate orders in an extended-care study group.

We examined the charts of 911 nursing home patients in Hennepin County, Minnesota, to determine the prevalence of written do-not-resuscitate (DNR) orders. Information regarding demographic characteristics, and whether a surrogate decisionmaker was available and participated in the decision, was also collected. Twenty-seven percent of patients had DNR orders. Ninety percent of all patients had potentially available surrogate decisionmakers. However, for 31% of patients with DNR orders, there was no documentation of patient or surrogate participation in the DNR decision. Univariate analysis identified female sex; increased age, level of care (skilled versus intermediate), presence of a potential surrogate decisionmaker, and increasing length of time since nursing home admission as factors associated with presence of DNR orders. When a logistic regression model was used, increased age, increased length of time since nursing home admission, skilled versus intermediate level of care, and presence of a surrogate decisionmaker were independently associated with presence of DNR status. Several variables are independently associated with written DNR orders; their relationship to the factors physicians use in decision making requires further study.

Age Factors↗

PubMed2025

Optimizing genetic ancestry adjustment in DNA methylation studies: a comparative analysis of approaches.

BACKGROUND: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry. METHODS: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control probe PCs, sex, age, and cell type proportions to remove the effects of technical and biological factors, and (2) integrating the residualized data with genotype calls from the SNP probes (commonly referred to as rs probes) present on the arrays, before calculating PCs and evaluated the clustering ability and relationship to genetic ancestry. RESULTS: The PCs generated by EpiAnceR+ led to improved clustering for repeated samples from the same individual and stronger associations with genetic ancestry groups predicted from genotype information compared to the original approach. EpiAnceR+ also outperformed the use of DNA methylation PCs or surrogate variables for ancestry adjustment. CONCLUSIONS: We show that the EpiAnceR+ approach improves the adjustment for genetic ancestry in DNA methylation studies. EpiAnceR+ can be integrated into existing R pipelines for commercial methylation arrays, such as 450 K, EPIC v1, and EPIC v2. The code is available on GitHub ( https://github.com/KiraHoeffler/EpiAnceR ).

DNA Methylation↗

PubMed1992

Statistical model to determine the relationship of response and survival in patients with advanced ovarian cancer treated with chemotherapy.

BACKGROUND: A statistically appropriate analysis of the association between survival and response measures in patients with ovarian cancer could help to define the role of response rate in planning, monitoring, and interpreting the results of clinical trials. PURPOSE: This study was designed to investigate the relationship between antitumor response determined by clinical or pathological means and survival in patients with advanced ovarian cancer with no previous treatment. We focused on avoiding the limitations of the usual approach of comparing durations of survival for patients responding to therapy with those for nonresponders. METHODS: A new meta-analytic statistical model we developed was used to analyze data from 26 randomized clinical trials published between 1975 and 1989. Our model incorporates intra-study and inter-study sources of variability in the estimates of response and survival. The study also addresses the methodological problems of evaluating response as a surrogate end point and the relevance of this association to clinical decision making and the design of clinical trials. RESULTS: For 13 studies in which response was pathologically assessed, an improvement in surgically documented complete response rate was associated with an increase in median survival. A similar but apparently smaller effect was found for the association between objective clinical response and median survival in the 25 studies reporting these data. CONCLUSIONS: These results suggest that therapeutic measures must produce large improvements in clinical response rates to achieve meaningful effects on median survival. Improvement in surgically documented complete response rate appears to be more strongly associated with increased median survival and, hence, might be used for interim monitoring in clinical trials, but the role of second-look procedures in clinical management is controversial.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

An assessment of the usefulness of demographic data provided by surrogate respondents in a case-control study of Parkinson's disease.

This study, based upon data from 40 non-demented Parkinson's disease cases and 101 community controls, and similar data provided by either the spouse (n = 110) or an adult child (n = 31) of each index subject, attempted to assess the usefulness of various demographic data provided by the surrogate respondents for the index subjects. The data were collected by personal interview using a structured questionnaire specifically developed for this study. Ninety-one percent of the index subjects and their surrogates provided information on the annual family income and 98% provided other demographic information. The analysis was done by three groups: the case-surrogates, the control-surrogates and the combined index subject-surrogates, and within each group by the two types of surrogates for the index subjects: the spouse vs adult child. The overall percent agreement between the index subjects and their surrogates varied from moderate for annual family income (54.1%), to good for educational level (61.6%) and to excellent for ethnic origin (82.6%), for age +/- 1 year (97.9%) and for marital status (100.0%). No significant differences in agreement were found for any of these demographic variables either between the case-surrogate group and the control-surrogate group, or between the spouse surrogates and the child surrogates. These findings suggest that spouses and adult children can provide valid information and are equally reliable informants concerning the demographic characteristics of index subjects in a case-control study of Parkinson's disease and, possibly, of other diseases.

Age Factors↗

PubMed1992

Heated dorsal hand vein sampling for metabolic studies: a reappraisal.

The purpose of the current study was to determine the accuracy of a given heated dorsal hand vein (HDHV) measurement in predicting a simultaneous arterial measurement and to validate this technique for use in stable isotope studies. Twenty catheterizations of the femoral artery, femoral vein, and a dorsal hand vein were performed in 13 healthy male subjects. Simultaneous blood samples were obtained from all three sites during primed continuous infusions of L-[1-13C]leucine (Leu) and L-[ring-2H5]phenylalanine (Phe) in the postabsorptive state, with or without intravenous glucose infusion. Relationships were examined by linear regression analysis, with 95% prediction intervals for femoral arterial values determined using the HDHV-derived values as independent variable. Glucose concentrations and isotopic enrichments of ketoisocaproate (KIC), Leu, and Phe were similar in HDHV- and arterial-derived blood, with slopes between 0.9414 and 1.0008, intercepts not different from zero, and r2 values of 0.7613 or greater (P < 0.05). Intercepts for KIC, Leu, and Phe concentrations all were different from zero (P < 0.05), and slopes ranged between 0.7560 and 0.8625. For each analysis the HDHV sample correlated better with the femoral arterial sample than with the femoral venous sample. These data support the use of HDHV sampling as a surrogate for direct arterial sampling but document significant limitations in the technique.

Adult↗

PubMed1989

An assessment of peak expiratory flow as a surrogate measurement of FEV1 in stable asthmatic children.

We examined the relationship over 24 hours between percent-predicted values (PPV) of peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) in a group of 23 stable untreated asthmatic children 6 to 17 years of age by means of regression analysis as well as the percentage difference between the PPV of these two measurements. Although the Pearson correlation coefficient between the PPV was consistently high, ranging between 0.854 and 0.892, the assumption that such a finding substantiates the substitution of PEF for FEV1 is called into question. Over 50 percent of the subjects displayed a 10 percent or greater difference in the PPV between the two measurements, regardless of the time of day the two respiratory variable were determined, while over one-third of all subjects evidenced a 20 percent or greater discrepancy between the PPV of the two measures. While, on a group basis, there was no statistically significant difference in the mean percentage difference over 24 hours between the PPV of FEV1, when compared with the corresponding measurement of PEF, reliance on PEF alone in individual subjects may result in a false impression of the patency of the airways in comparison to the FEV1.

Adolescent↗