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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↗

PubMedDate not supplied

Approximate entropy and point correlation dimension of heart rate variability in healthy subjects.

The contribution of nonlinear dynamics to heart rate variability in healthy humans was examined using surrogate data analysis. Several measures of heart rate variability were used and compared. Heart rates were recorded for three hours and original data sets of 8192 R-R intervals created. For each original data set (n = 34), three surrogate data sets were made by shuffling the order of the R-R intervals while retaining their linear correlations. The difference in heart rate variability between the original and surrogate data sets reflects the amount of nonlinear structure in the original data set. Heart rate variability was analyzed by two different nonlinear methods, point correlation dimension and approximate entropy. Nonlinearity, though under 10 percent, could be detected with both types of heart rate variability measures. More importantly, not only were the correlations between these measures and the standard deviation of the R-R intervals weak, the correlation among the nonlinear measures themselves was also weak (generally less than 0.6). This suggests that in addition to standard linear measures of heart rate variability, the use of multiple nonlinear measures of heart rate variability might be useful in monitoring heart rate dynamics.

Adult↗

PubMed1994

Gingival recession: intra-oral distribution and associated factors.

This study assesses the role of poor oral hygiene and forceful toothbrushing as risk factors for recession. As part of a cross-sectional root surface caries study, 298 subjects, 42 to 67 years of age, with at least one exposed root surface, were examined. Since 66% of the root surface exposure and practically all the abrasion was on buccal surfaces, the analyses focused only on the buccal surface. Analysis of variance on subject means for buccal recession showed both calculus and presence of buccal root surfaces with abrasion to be significantly associated with recession after adjusting for age and gender. Root surface abrasion was considered a surrogate variable for forceful brushing. An additional analysis utilized means for each tooth, aggregating across subjects. For each of the 32 tooth types mean buccal recession, percent of exposed root surfaces with abrasion (%ra), and mean debris and calculus scores were calculated. Partial correlation coefficients across tooth types between recession and calculus, adjusting for abrasion, and for recession and abrasion adjusting for calculus, were 0.55. Interpretation of the %ra as a crude measure of forceful brushing is supported by its strong negative correlation across tooth types, with mean debris (r = -0.8) and mean calculus (r = -0.7). Separate analyses on premolars and on molars suggested that recession on premolars may be primarily due to brushing force and on the molars may be primarily due to debris and calculus. The findings suggest that recession is positively associated with percent abrasion (reflecting forceful brushing) and with poor oral hygiene.

Adult↗

PubMedDate not supplied

Some issues in estimating the effect of prognostic factors from incomplete covariate data.

In evaluating prognostic factors by means of regression models, missing values in the covariate data are a frequent complication. There exist statistical tools to analyse such incomplete data in an efficient manner, and in this paper we make use of the traditional maximum likelihood principle. As well as an analysis including the incompletely measured covariates, such tools also allow further strategies of data analysis. For example, we can use surrogate variables to improve the prediction of missing values or we can try to investigate a questionable "missing at random' assumption. We discuss these techniques using the example of a clinical study where one important covariate is missing for about half the subjects. Additionally we consider two further issues: evaluation of differences between estimates from a complete case analysis and analyses using all subjects and assessment of the predictive value of missing values.

Data Interpretation, Statistical↗

PubMed2001

Correlations among time and frequency measures of heart rate variability recorded by use of a Holter monitor in overtly healthy Doberman pinschers with and without echocardiographic evidence of dilated cardiomyopathy.

OBJECTIVE: To determine correlations between time-domain and frequency-domain variables of heart rate variability (HRV) derived from 24-hour recordings obtained by use of an ambulatory electrocardiographic recorder (Holter monitor). ANIMALS: 59 overtly healthy Doberman Pinschers (41 without echocardiographic evidence of cardiomyopathy and 18 with precongestive heart failure attributable to cardiomyopathy). PROCEDURE: The HRV was analyzed from 24-hour recordings. Variables were calculated from the entire 24-hour recording as well as 4 user-selected time epochs. Comparisons were made for total power to SD of normal beat-to-normal-beat (NN) intervals (SDNN), ultra-low frequency power to SD of the means of NN intervals, low-frequency power and very-low-frequency power to mean of the SD of NN intervals, and high-frequency (HF) power to the root mean square successive difference of NN intervals (RMSSD) and percentage of NN intervals that varied from the previous NN interval by > 50 milliseconds (PNN50). RESULTS: 58 of 66 (88%) comparisons revealed significant values, indicating that relationships between variables were not random (r > 0.7 in 41 of 66 [62%)) comparisons). Strong correlations (r > 0.8) were found between the square root of total power and SDNN and between HF power and RMSSD. CONCLUSIONS AND CLINICAL RELEVANCE: Time-domain surrogates for variables of frequency-domain analysis variables that correlated in the dogs reported here are the same ones that reportedly correlate in humans. When 24-hour recordings obtained by use of a Holter monitor are used to calculate HRV, SDNN and total power as well as RMSSD and HF power are interchangeable.

Animals↗

PubMed2001

Estrogens and falling sperm counts.

Extravagant claims have been made repeatedly in recent years that human sperm counts are falling and that global exposure to environmental estrogens are responsible. The basis for these two distinct claims is reviewed. The claims of falling human sperm output, reviving an old debate, are prompted by a paper by Carlsen et al. (1992). This meta-analysis, however, is marred by numerous flaws that invalidate its claims. Major defects include severe heterogeneity of component studies, rendering them unsuitable for aggregation, and defective data analysis based on arithmetic mean rather than median, which showed no significant changes over time. This debate is likely to remain unresolved until valid, representative population-based studies of human sperm output can be achieved. None have been reported, or seem feasible in the near future, and so alternative strategies, based on surrogate variables for human male fertility not requiring sperm counts, need to be developed and validated. The plausible hypothesis that prenatal estrogen exposure might influence development of the human testis through effects on Sertoli cell replication and sperm carrying capacity has, however, been conclusively refuted by studies of boys born to women exposed to high doses of oral diethylstilbestrol during pregnancy. Neither fertility nor sperm output were adversely influenced by massive maternal estrogen exposure during pregnancy, although minor urogenital malformations did occur. The still wider claims of deteriorating male reproductive health, notably changes in prevalence or incidence of hypospadias or cryptorchidism, also lack convincing population-based evidence, although cancer registry data indicate a gradual increase in testis cancer in some countries. In summary, the available evidence does not support claims of falling sperm counts or any general deterioration in male reproductive health. Population-based studies of valid surrogate variables for male fertility not requiring semen analysis are needed. If population-based evidence regarding male fertility or sperm output could be generated, it is highly unlikely that prenatal estrogen exposure could be a valid explanation of any deterioration as massive maternal exposure to oral estrogen has negligible effects on male fertility or sperm output.

Estrogens↗

PubMed2004

Surrogate data analysis for assessing the significance of the coherence function.

In cardiovascular variability analysis, the significance of the coupling between two time series is commonly assessed by setting a threshold level in the coherence function. While traditionally used statistical tests consider only the parameters of the adopted estimator, the required zero-coherence level may be affected by some features of the observed series. In this study, three procedures, based on the generation of surrogate series sharing given properties with the original but being structurally uncoupled, were considered: independent identically distributed (IID), Fourier transform (FT), and autoregressive (AR). IID surrogates maintained the distribution of the original series, while FT and AR surrogates preserved the power spectrum. The ability of the three methods to define the threshold for zero coherence was validated and compared by computer simulations reproducing typical cardiovascular interactions. While the IID threshold depended only on record length and design parameters of the coherence estimator, FT and AR thresholds were frequency-dependent with peaks corresponding to the local maxima of the estimated coherence. FT and AR surrogates were able to compensate spurious coherence peaks due to equal-frequency but independent oscillations in the two series. The benefit of frequency-dependent thresholds was evident for short series with narrow-band oscillations. Thus, surrogates preserving the power spectrum of the original series are recommended to avoid false coupling detections in the presence of oscillations occurring at nearby frequencies but produced by different mechanisms, as may frequently happen in cardiovascular and cardiorespiratory regulation.

Algorithms↗

PubMed2006

The flawed basis for FDA post-marketing safety decisions: the example of anti-depressants and children.

The FDA (February 3, 2005) issued a black box warning that all antidepressants increase the risk of suicidal thinking and behavior in children and adolescents that must be cited in all advertising as well as included in the package insert. Following this, there was a sharp decrease in antidepressant prescriptions for children with uncertain public health impact. The current black box does not claim that these medications increase the risk of completed suicides, although this is the clear implication of the term 'suicidality'. The interpretation by the press is unequivocal that lethal outcomes prompted this action. This review concludes the following: (1) Since no suicide occurred in clinical trials of approximately 4400 children, the analyses relied upon 'suicidality' as a surrogate. (2) The classification of adverse events by the Columbia group necessarily relied on inferences, because the available evidence was not prospectively collected for this purpose. (3) The data analysis relied on a composite variable labeled 'suicidality', an unvalidated, inappropriate surrogate. Specific criticisms of analytic procedures and inferences are presented. The failure of the FDA's post-marketing surveillance system is reviewed. The data necessary for objective evaluations of possible post-marketing harm cannot be gathered by the current process. Proper prospective post-marketing surveillance by linked computerized medical records is a crucial issue that deserves major public and political attention and prompt action.

Adverse Drug Reaction Reporting Systems↗

PubMed2002

Factor analysis of metabolic syndrome using directly measured insulin sensitivity: The Insulin Resistance Atherosclerosis Study.

Factor analysis, a multivariate correlation technique, has been used to provide insight into the underlying structure of metabolic syndrome, which is characterized by physiological complexity and strong statistical intercorrelation among its key variables. The majority of previous factor analyses, however, have used only surrogate measures of insulin sensitivity. In addition, few have included members of multiple ethnic groups, and only one has presented results separately for subjects with impaired glucose tolerance. The objective of this study was to investigate, using factor analysis, the clustering of physiologic variables using data from 1,087 nondiabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). This study includes information on the directly measured insulin sensitivity index (S(I)) from intravenous glucose tolerance testing among African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years at various stages of glucose tolerance. Principal factor analysis identified two factors that explained 28 and 9% of the variance in the dataset, respectively. These factors were interpreted as 1) a " metabolic" factor, with positive loadings of BMI, waist, fasting and 2-h glucose, and triglyceride and inverse loadings of log(S(I)+1) and HDL; and 2) a "blood pressure" factor, with positive loadings of systolic and diastolic blood pressure. The results were unchanged when surrogate measures of insulin resistance were used in place of log(S(I)+1). In addition, the results were similar within strata of sex, glucose tolerance status, and ethnicity. In conclusion, factor analysis identified two underlying factors among a group of metabolic syndrome variables in this dataset. Analyses using surrogate measures of insulin resistance suggested that these variables provide adequate information to explore the underlying intercorrelational structure of metabolic syndrome. Additional clarification of the physiologic characteristics of metabolic syndrome is required as individuals with this condition are increasingly being considered candidates for behavioral and pharmacologic intervention.

Arteriosclerosis↗

PubMed1994

Construction of a surrogate variable for impotence in the Massachusetts Male Aging Study.

Uncollected data must be filled in after the fact in many epidemiological studies. We compared several methods for constructing a surrogate variable for erectile potency, based on responses to related questions, in the Massachusetts Male Aging Study (MMAS). Quadratic discriminant analysis performed best among the procedures tested, achieving high rates of correct classification in cross-validation of training data and (according to posterior estimates) in classification of MMAS subjects. Two versions of the surrogate variable were constructed, one involving a discrete classification and the other involving a set of continuous probabilities. The two versions were used to investigate medical correlates of impotence in MMAS and produced similar results, although the continuous version appeared to provide higher statistical power. We conclude that construction of a surrogate variable is a viable and potentially beneficial option in epidemiological investigations.

Adult↗

PubMed2005

Proposal for a multidimensional staging system for chronic obstructive pulmonary disease.

The severity of chronic obstructive pulmonary disease (COPD) is currently assessed using a single physiological measurement, the forced expiratory volume in 1s (FEV1). COPD, however, has complex effects on other aspects of respiratory function, and in many patients is associated with important systemic changes. We hypothesized that a multidimensional staging system for COPD could provide a more complete assessment of the disease's impact. We considered over 40 potential staging variables, evaluating them according to sensitivity to change, measured reproducibly, independence of the information they provide and prognostic value. We finally selected three: FEV1 (including arterial blood gas measurements when FEV1 falls below 35% predicted), Medical Research Council dyspnea scale and body mass index (BMI). Each measure correlates independently with prognosis in COPD, is supported by a significant body of literature and serves as a surrogate for other potentially important variables. We then used principal components analysis (PCA) to determine the degree of association between 30 of the potential variables measured in 813 stable COPD patients. Using PCA, six groups of measurements defined independent categories of patient information: pulmonary function (including FEV1), symptoms of cough and sputum, dyspnea, health status, bronchodilator reversibility and BMI. These include the three principal variables selected for the staging system. Although the staging boundaries were based on existing literature, they have proven useful in predicting survival. We conclude that a multidimensional grading system is useful to assess the impact of COPD.

Age Factors↗

PubMed2005

Outcomes following liver transplantation for seronegative acute liver failure: experience during a 12-year period with more than 100 patients.

Seronegative hepatitis is a common cause of acute liver failure (ALF) requiring liver transplantation. The primary aim of this study was to examine outcomes following transplantation in this group and to identify factors associated with early (<2 months) mortality. Patients studied were 110 consecutive cases of seronegative ALF transplanted at the Queen Elizabeth Hospital, Birmingham, between January 1992 and January 2004. Univariate analysis of 44 pretransplantation recipient, donor, and operative variables was performed initially to identify factors associated with early posttransplantation mortality. Variables identified as significant or approaching significance were analyzed using stepwise multiple logistic regression analysis. Survival following transplantation for seronegative hepatitis was 83%, 81%, and 73% at 2, 12, and 60 months, respectively. The majority (71%) of deaths occurred within the 1st 2 months and sepsis / multiorgan dysfunction was the most common cause of early death. Univariate analysis revealed 9 variables predicting early death. Subsequent multivariate analysis identified high donor body mass index (BMI; a possible surrogate marker for hepatic steatosis) as the most important predictor of early death (P = .009; odds ratio, 1.2; 95% confidence interval, 1.0-1.3). Recipient age >50 (P = .015; odds ratio, 4.2; 95% confidence interval, 1.3-14.1) and non-Caucasian recipient ethnicity (P = .015; odds ratio, 4.9; 95% confidence interval, 1.2-19.2) were other variables associated with early death on multivariate analysis. This study specifically examined factors that determine the early outcome of transplanted seronegative ALF patients. In conclusion, we found that donor and recipient factors identify patients who have a high chance of early death after transplantation.

Adolescent↗

PubMed2002

Time-dependent structure in the discharge rate of human motor units.

OBJECTIVES: The aim of this study was to examine the influence of visual and motor processes on the deterministic and stochastic structure of force output and motor unit discharge variability. METHODS: Young adult subjects produced continuous, isometric force at 3, 6, 12, and 24% of their maximal voluntary contraction at low and high visual gain levels through abduction of the index finger. Force and fine-wire intramuscular electromyography were recorded. RESULTS: There was a linear increase in discharge irregularity with increases in the mean motor unit discharge rate (8-30 Hz). Recurrence analysis showed that the percentage of deterministic structure in discharge variability remained high, but decreased linearly with increased motor unit discharge rate. Surrogate analyses confirmed that the motor unit discharge variability was inconsistent with an uncorrelated and linearly correlated Gaussian noise process. Spectral analysis revealed that both the force output and the mean time-varying motor unit discharge time series had a dominant frequency of 0-2 Hz. Visual feedback gain did not affect the individual motor unit discharge patterns. CONCLUSIONS: The motor unit discharge rate has deterministic time-dependent structure. The motor unit discharge rate is modulated at multiple time scales likely by pre- and post-synaptic induced fluctuations from spinal level pathways impinging on the motor neuron.

Action Potentials↗

PubMed2005

Audiometric threshold shift definitions: simulations and suggestions.

OBJECTIVES: Determine (1) whether pure-tone average (PTA) or "any frequency" (AF) definitions of significant threshold shift (STS) are more accurate under different conditions; (2) whether STS definitions applied twice are more accurate than when applied once; (3) whether three surrogate analysis methods applicable to real-world audiometric data can appropriately measure the accuracy of STS definitions; and (4) whether evidence from previous studies supports a change in the current STS definition used by the Occupational Safety and Health Administration (OSHA); (5) make recommendations for future research. DESIGN: Computer simulation of periodic audiograms, with typical test-retest variability, from seven groups of individuals (N = 1000 each), with or without threshold shifts of different sizes at different frequencies; receiver operating characteristic area analysis to determine relative accuracy of PTA and AF decision variables, applied once or twice; testing of surrogate methods (confirmation, variability, and comparison) against receiver operating characteristic areas in estimation of accuracy of decision variables; review of previous studies, considering the limitations of the surrogate methods that were used. RESULTS: Either AF or PTA definitions may be preferable, depending on whether the genuine threshold shift has occurred at a single frequency or across a range of frequencies. Including too few or too many frequencies degrades the performance of both AF and PTA variables. An STS decision variable performs only slightly better when applied twice than when applied once. The surrogate methods can be useful, but all have important caveats: The comparison method is best, but only when an appropriate control group is available; the variability method is intermediate but requires that each decision variable be tested at multiple criterion values for reliable results. The confirmation method, which was the least accurate in assessing true performance, also requires testing at multiple levels. Even when this is done, it markedly exaggerates the benefit of applying an STS definition twice and makes STS definitions that identify large numbers of individuals falsely appear to be more accurate than definitions that identify smaller numbers of individuals. Taking these caveats into account, previous studies do not offer convincing evidence for a change in the current OSHA STS definition. CONCLUSIONS: Choice of an STS definition requires three judgments that cannot be made based on the type of analysis discussed in this report: The range of frequencies to be tested, whether to require that an STS definition be applied twice, and the acceptable magnitude of false-positive error. Once these judgments have been made, the techniques discussed here can assist in selecting the appropriate decision variable (typically PTA or AF) and a criterion value that yields an acceptable false-positive rate. Additional research using the techniques described in this report with either new or old audiometric databases could help determine whether any STS definition is significantly better than the current OSHA definition.

Audiometry, Pure-Tone↗

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↗

PubMed2000

Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes.

AIMS/HYPOTHESIS: Non-alcoholic steatohepatitis is frequent in Type II (non-insulin-dependent) diabetes mellitus and can lead to fibrosis and cirrhosis. The interindividual variability in the occurrence of nonalcoholic steatohepatitis suggests, however, a genetic modulation. Microsomal triglyceride transfer protein (MTP) is necessary for the assembly and secretion of VLDL and when the protein is not functional, such as in abetalipoproteinaemia, a steatohepatitis occurs. We therefore assessed the association between a functional polymorphism in the promoter region of MTP gene (-493 G/T) and the biological features of steatohepatitis in Type II diabetic patients. METHODS: We studied 271 patients with Type II diabetes. Determination of -493 G/T polymorphism was made by PCR-RFLP. Increased liver enzymes were used as surrogates of liver steatosis and alanine aminotransferase concentration was the outcome variable for the multivariate analysis. Liver ultrasonography was available for a subgroup of patients with newly diagnosed diabetes. RESULTS: The proportion of patients with increased alanine aminotransferase was higher in GG than in GT and TT subgroups (23%, 11% and 6%, respectively, p = 0.01). Additionally, patients with high alanine aminotransferase concentrations were more likely to be young (p = 0.01), male (p = 0.001), obese (p = 0.04) and have low HDL-cholesterol (p = 0.01). In multivariate analysis, the MTP genotype was independently associated with alanine aminotransferase concentration (p = 0.0023) as well as sex and body mass index but not HDL-cholesterol. CONCLUSION/INTERPRETATION: The -493 G/T MTP gene polymorphism is associated with biological surrogates of steatohepatitis in patients with Type II diabetes. The G allele which is responsible for a decrease in MTP gene transcription is prone to increase the intrahepatic triglycerides content, conferring by this a genetic susceptibility for steatohepatitis.

Adult↗

PubMed2001

On the use of surrogate respondents for controls in a case-control study of Alzheimer's disease.

OBJECTIVE: To examine the presence and extent of bias introduced by using surrogate respondents for healthy controls in a case-control study of Alzheimer's disease (AD). DESIGN: Comparative study of matched responses to questionnaire ascertaining lifestyle issues. SETTING: University Hospitals/Case Western Reserve University Alzheimer Center. PARTICIPANTS: Controls (n = 50) were identified through the Research Registry. Surrogates (n = 50) were their healthy relatives or friends. MEASUREMENTS: Answers in the areas of demographic and occupational history, smoking habits, medical history, dietary intake, and leisure and work activities were recorded. The analysis was based on methods for paired data. Continuous variables were analyzed, focusing on paired differences between self and surrogate responses. RESULTS: For occupations and exposures, over 80% of the surrogates agreed with the subjects on over 80% of the questions. On smoking history, over 90% of the surrogates agreed with the subjects on over 70% of the questions. On leisure and work activities, over 70% of the surrogates agreed with the subjects on over 50% of the questions. There was less agreement regarding medical history. For continuous variables, most paired t-tests of zero mean difference between self and surrogate responses resulted in nonrejection of this hypothesis. Computed mean differences were not always positive or always negative. CONCLUSION: We did not find systematic under- or overreporting by the surrogates of the controls. Therefore, if there are biases in the responses of surrogates of the AD cases in our case-control study, they would not be canceled out by using surrogates for the controls.

Aged↗