Affected Sib Pair Tests in Inbred Populations

The affected‐sib‐pair (ASP) method for detecting linkage between a disease locus and marker loci was first established 50 years ago, and since then numerous modifications have been made. We modify two identity‐by‐state (IBS) test statistics of Lange ( Lange, 1986a, 1986b ) to allow for inbreeding in the population. We evaluate the power and false positive rates of the modified tests under three disease models, using simulated data. Before estimating false positive rates, we demonstrate that IBS tests are tests of both linkage and linkage disequilibrium between marker and disease loci. Therefore, the null hypothesis of IBS tests should be no linkage and no LD. When the population inbreeding coefficient is large, the false positive rates of Lange's tests become much larger than the nominal value, while those of our modified tests remain close to the nominal value. To estimate power with a controlled false positive rate, we choose the cutoff values based on simulated datasets under the null hypothesis, so that both Lange's tests and the modified tests generate same false positive rate. The powers of Lange's z‐test and our modified z‐test are very close and do not change much with increasing inbreeding. The power of the modified chi‐square test also stays stable when the inbreeding coefficient increases. However, the power of Lange's chi‐square test increases with increasing inbreeding, and is larger than that of our modified chi‐square test for large inbreeding coefficients. The power is high under a recessive disease model for both Lange's tests and the modified tests, though the power is low for additive and dominant disease models. Allowing for inbreeding is therefore appropriate, at least for diseases known to be recessive.     

On the validity of the likelihood ratio test and consistency of resulting parameter estimates in joint linkage and linkage disequilibrium analysis under improperly specified parametric models

It has been shown that parametric analysis of linkage disequilibrium conditional on linkage using an overly deterministic model can be optimal for family-based association analysis. However, if one applies this strategy carelessly, there is a risk of false inference. We analyse properties of such likelihood ratio tests when the assumed disease mode of inheritance is inaccurate. Under some conditions, problems result if one is not careful to consider what null hypothesis is being tested. We show that: (a) tests for which the null hypothesis assumes the absence of both linkage and association are independent of the true mode of inheritance; (b) likelihood ratio tests assuming either linkage or association under the null hypothesis may depend on the true mode of inheritance, leading to inconsistent parameter estimates, in particular under extremely deterministic models; (c) this problem cannot be eliminated by increasing sample size or adding population controls--as sample size increases, the chance of false positive inference goes to 100%; (d) this issue can lead to systematic false positive inference of association in regions of linkage. This is important because highly deterministic models are often used intentionally in model-based analyses because they can have more power than the true model, and are implicit in many model-free analysis methods.     

Perceptual false recognition in Alzheimer's disease

Previous research has found that patients with probable Alzheimer's disease (AD) show lower levels of false recognition of semantic associates than do healthy older adults. To investigate whether this finding is attributable to semantic impairments in patients with AD, the authors examined false recognition of perceptually related novel objects with little semantic content in patients with AD and healthy older adults. By using corrected recognition scores to control for unrelated false alarms, it was found that patients with AD showed lower levels of both true and false recognition of novel objects than did older adults. These results suggest that the previous difference in false recognition of semantic associates observed between patients with AD and older adults is not entirely attributable to semantic memory deficits in patients with AD but may also involve poorly developed gist information in these patients.     

Wavelet method for CT colonography computer-aided polyp detection

Computed tomographic colonography (CTC) computer aided detection (CAD) is a new method to detect colon polyps. Colonic polyps are abnormal growths that may become cancerous. Detection and removal of colonic polyps, particularly larger ones, has been shown to reduce the incidence of colorectal cancer. While high sensitivities and low false positive rates are consistently achieved for the detection of polyps sized 1 cm or larger, lower sensitivities and higher false positive rates occur when the goal of CAD is to identify "medium"-sized polyps, 6-9 mm in diameter. Such medium-sized polyps may be important for clinical patient management. We have developed a wavelet-based postprocessor to reduce false positives for this polyp size range. We applied the wavelet-based postprocessor to CTC CAD findings from 44 patients in whom 45 polyps with sizes of 6-9 mm were found at segmentally unblinded optical colonoscopy and visible on retrospective review of the CT colonography images. Prior to the application of the wavelet-based postprocessor, the CTC CAD system detected 33 of the polyps (sensitivity 73.33%) with 12.4 false positives per patient, a sensitivity comparable to that of expert radiologists. Fourfold cross validation with 5000 bootstraps showed that the wavelet-based postprocessor could reduce the false positives by 56.61% (p <0.001), to 5.38 per patient (95% confidence interval [4.41, 6.34]), without significant sensitivity degradation (32/45, 71.11%, 95% confidence interval [66.39%, 75.74%], p=0.1713). We conclude that this wavelet-based postprocessor can substantially reduce the false positive rate of our CTC CAD for this important polyp size range.     

The Amino Acid Sequence of Neisseria lactamica PorB Surface-Exposed Loops Influences Toll-Like Receptor 2-Dependent Cell Activation

Toll-like receptors (TLRs) play a major role in host mucosal and systemic defense mechanisms by recognizing a diverse array of conserved pathogen-associated molecular patterns (PAMPs). TLR2, with TLR1 and TLR6, recognizes structurally diverse bacterial products such as lipidated factors (lipoproteins and peptidoglycans) and nonlipidated proteins, i.e., bacterial porins. PorB is a pan-neisserial porin expressed regardless of organisms' pathogenicity. However, commensal Neisseria lactamica organisms and purified N. lactamica PorB (published elsewhere as Nlac PorB) induce TLR2-dependent proinflammatory responses of lower magnitude than N. meningitidis organisms and N. meningitidis PorB (published elsewhere as Nme PorB). Both PorB types bind to TLR2 in vitro but with different apparent specificities. The structural and molecular details of PorB-TLR2 interaction are only beginning to be unraveled and may be due to electrostatic attraction. PorB molecules have significant strain-specific sequence variability within surface-exposed regions (loops) putatively involved in TLR2 interaction. By constructing chimeric recombinant PorB loop mutants in which surface-exposed loop residues have been switched between N. lactamica PorB and N. meningitidis PorB, we identified residues in loop 5 and loop 7 that influence TLR2-dependent cell activation using HEK cells and BEAS-2B cells. These loops are not uniquely responsible for PorB interaction with TLR2, but NF-κB and MAP kinases signaling downstream of TLR2 recognition are likely influenced by a hypothetical "TLR2-binding signature" within the sequence of PorB surface-exposed loops. Consistent with the effect of purified PorB in vitro, a chimeric N. meningitidis strain expressing N. lactamica PorB induces lower levels of interleukin 8 (IL-8) secretion than wild-type N. meningitidis, suggesting a role for PorB in induction of host cell activation by whole bacteria.     

Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants

This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P = 6.94E - 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOEepsilon4 and epsilon2/3 variants (0.09 < D'<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006; odds ratio (OR) = 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P = 0.00005, OR = 1.2, false positive rate = 0.87).     

Use of haplotype information to test involvement of the LRP gene in Alzheimer's disease in the French population.

The low density lipoprotein receptor-related protein gene (LRP) is a good candidate gene for Alzheimer's Disease (AD). Its protein is involved in the physiopathology of AD and has been found in senile plaques; on the other hand, LRP is located in 12q, a region in which genetic linkage to AD was reported. Two common polymorphisms, a tetranucleotide repeat in the 5' untranslated region and a single nucleotide polymorphism at position 766 in exon 3, were found to be associated with AD, but contradictory results were obtained in subsequent association studies. In the absence of clear hypotheses concerning the association of these polymorphisms with AD and their functional role, our objective was to test the association between AD and the two LRP polymorphisms in a large French case-control sample (274 Caucasian AD patients and 290 matched controls) using haplotype analysis. First, the separate study of each polymorphism showed no significant difference in genotype and allele frequencies between AD cases and controls. Second, strong linkage disequilibrium was found between alleles of the two polymorphisms in controls and in cases and the linkage disequilibrium between the 91 bp and C alleles were opposite in cases and in controls. Third, we found that the frequency of the 91-C haplotype was higher in cases than in controls, but the type I error was 0.061, slightly higher than the conventional one of 5%. The haplotype frequencies did not vary significantly as a function of age and APOE epsilon4 status. One interest in this study is the use of the haplotype analysis, which can be used to combine information from several polymorphisms, taking into account their dependence.     

PSEN1 polymorphisms alter the rate of cognitive decline in sporadic Alzheimer's disease patients

Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimer's disease (AD), which account for around 5% of AD cases. Genetic associations for the remaining “sporadic” cases, other than the risks associated with the apolipoprotein (APOE) 4 allele are currently not fully established. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in PSEN1 are associated with a modified risk for sporadic AD or a modified disease phenotype. Eight tag SNPs were identified using linkage disequilibrium (LD) data from the International HapMap project providing coverage of the entire PSEN1 gene. These SNPs were investigated for AD susceptibility in a case-control haplotype association study (N = 714) and for genotype-specific effects on cognitive performance in AD patients (N = 169) using non-linear mixed effects modelling. Replication of a mild associated-risk of an intronic PSEN1 polymorphism with AD was achieved (P = 0.03). No other single SNPs or haplotypes were associated with AD risk. However, 3 SNPs were associated with an altered rate of cognitive decline underlining their role as genetic modifiers of disease.     

Dermatoglyphic patterns in Alzheimer's disease

Selected dermatoglyphic variables were analyzed in 50 patients with presumed Alzheimer's disease (AD), 50 patients with dementia referable to other causes, and 100 control patients without known dementia matched for age, sex, and race. AD patients have a significantly increased frequency of ulnar loops on the fingertips, Simian creases on the palms, palmar hypothenar patterns; and large distal loops in the hallucal region. A trend involving an increased frequency of radial loops on the fourth and fifth digits, Sydney lines on the palms, and small distal loops on the soles was also observed. The presence of eight or more ulnar loops or bilateral hypothenar patterns separates AD patients from controls with 84% sensitivity and 63% specificity, supporting the discriminant value of dermatoglyphics in the categorization of patients and in the potential identification of asymptomatic persons at increased risk for AD by dermatoglyphic criteria. The dermatoglyphic patterns observed in the AD patients correspond remarkably with patterns repeatedly observed in Down's syndrome and parents of Down's syndrome children, suggesting that a common genetic factor modulates epidermal ridge formation during fetal development, meiotic non-disjunction during gametogenesis, and accelerated neuronal senescence.     

Impact of linkage quality on inferences drawn from analyses using data with high rates of linkage errors in rural Tanzania

Background

Studies based on high-quality linked data in developed countries show that even minor linkage errors, which occur when records of two different individuals are erroneously linked or when records belonging to the same individual are not linked, can impact bias and precision of subsequent analyses. We evaluated the impact of linkage quality on inferences drawn from analyses using data with substantial linkage errors in rural Tanzania.

Methods

Semi-automatic point-of-contact interactive record linkage was used to establish gold standard links between community-based HIV surveillance data and medical records at clinics serving the surveillance population. Automated probabilistic record linkage was used to create analytic datasets at minimum, low, medium, and high match score thresholds. Cox proportional hazards regression models were used to compare HIV care registration rates by testing modality (sero-survey vs. clinic) in each analytic dataset. We assessed linkage quality using three approaches: quantifying linkage errors, comparing characteristics between linked and unlinked data, and evaluating bias and precision of regression estimates.

Results

Between 2014 and 2017, 405 individuals with gold standard links were newly diagnosed with HIV in sero-surveys (n =?263) and clinics (n =?142). Automated probabilistic linkage correctly identified 233 individuals (positive predictive value [PPV]?=?65%) at the low threshold and 95 individuals (PPV?=?90%) at the high threshold. Significant differences were found between linked and unlinked records in primary exposure and outcome variables and for adjusting covariates at every threshold. As expected, differences attenuated with increasing threshold. Testing modality was significantly associated with time to registration in the gold standard data (adjusted hazard ratio [HR] 4.98 for clinic-based testing, 95% confidence interval [CI] 3.34, 7.42). Increasing false matches weakened the association (HR 2.76 at minimum match score threshold, 95% CI 1.73, 4.41). Increasing missed matches (i.e., increasing match score threshold and positive predictive value of the linkage algorithm) was strongly correlated with a reduction in the precision of coefficient estimate (R² =?0.97; p =?0.03).

Conclusions

Similar to studies with more negligible levels of linkage errors, false matches in this setting reduced the magnitude of the association; missed matches reduced precision. Adjusting for these biases could provide more robust results using data with considerable linkage errors.

     

Effect of heterogeneity on the chromosome 10 risk in late-onset Alzheimer disease

With the exception of ApoE (APOE), no universally accepted genetic association has been identified with late-onset Alzheimer disease (AD). A broad region of chromosome 10 has engendered continued interest generated from both preliminary genetic linkage and candidate gene studies. To better examine this region, we combined unbiased genetic linkage with candidate gene association studies. We genotyped 36 SNPs evenly spaced across 80.2 Mb in a family-based data set containing 1,337 discordant sibling pairs in 567 multiplex families to narrow the peak region of linkage using both covariate and subset analyses. Simultaneously, we examined five functional candidate genes (VR22, LRRTM3, PLAU, TNFRSF6, and IDE) that also fell within the broad area of linkage. A total of 50 SNPs were genotyped across the genes in the family-based data set and an independent case-control data set containing 483 cases and 879 controls. Of the 50 SNPs in the five candidate genes, 22 gave nominally significant association results in at least one data set, with at least one positive SNP in each gene. SNPs rs2441718 and rs2456737 in VR22 (67.8 Mb) showed association in both family-based and case-control data sets (both P=0.03). A two-point logarithmic odds (LOD) score of 2.69 was obtained at SNP rs1890739 (45.1 Mb, P=0.03 in 21% of the families) when the families were ordered from low to high by ApoE LOD score using ordered subset analysis (OSA). These data continue to support a role for chromosome 10 loci in AD. However, the candidate gene and linkage analysis results did not converge, suggesting that there is more extensive heterogeneity on chromosome 10 than previously appreciated.     

Flow oscillations on the flow-volume loop: a nonspecific indicator of upper airway dysfunction

Flow oscillations on flow-volume loops (a "saw-tooth" pattern) have been reported as a manifestation of obstructive sleep apnea (OSA), but the specificity of this flow-volume loop pattern has not been determined. In a review of 2800 flow-volume loops performed in our pulmonary function laboratory, we identified flow oscillations in 40 patients, an incidence of 1.43%. Thirty-one of these 40 patients (77%) did not have OSA. In 16 of these 31 patients (52%), a structural disorder of the upper airway or neurologic disease involving the upper airway muscles was found. Flow oscillations were associated with physiological upper airway obstruction (UAO) in 14 of these 40 patients (35%), but were the only physiological evidence of upper airway dysfunction in the other 26 patients. Flow oscillations on flow-volume loops thus represent nonspecifically instability of the upper airway, caused by a variety of disorders, including OSA. Detection of this peculiar flow-volume loop configuration should lead to investigation of the upper airway and the surrounding musculature as it might be an early indicator of ongoing disorders eventually leading to UAO.     

Is There Any Role of Positron Emission Tomography Computed Tomography for Predicting Resectability of Gallbladder Cancer?

The role of integrated ¹⁸F-2-fluoro-2-deoxy-D-glucose positron emission tomography computed tomography (PET-CT) is uncertain in gallbladder cancer. The aim of this study was to show the role of PET-CT in gallbladder cancer patients. Fifty-three patients with gallbladder cancer underwent preoperative computed tomography (CT) and PET-CT scans. Their medical records were retrospectively reviewed. Twenty-six patients underwent resection. Based on the final outcomes, PET-CT was in good agreement (0.61 to 0.80) with resectability whereas CT was in acceptable agreement (0.41 to 0.60) with resectability. When the diagnostic accuracy of the predictions for resectability was calculated with the ROC curve, the accuracy of PET-CT was higher than that of CT in patients who underwent surgical resection (P=0.03), however, there was no difference with all patients (P=0.12). CT and PET-CT had a discrepancy in assessing curative resection in nine patients. These consisted of two false negative and four false positive CT results (11.3%) and three false negative PET-CT results (5.1%). PET-CT was in good agreement with the final outcomes compared to CT. As a complementary role of PEC-CT to CT, PET-CT tended to show better prediction about resectability than CT, especially due to unexpected distant metastasis.

Graphical Abstract

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Towards a theory of auditory hallucinations: outline of an hypothetical four-factor model.

The research findings of the writer to date on auditorily hallucinated patients are briefly summarized and an hypothetical four-factor model outlined to account for them. This general working model envisages auditory hallucinations as stemming from the interaction of psychological stress with an underlying hallucinatroy predisposition which is to a large extent genetically determined. A third factor of external stimulation is seen as exerting an inhibitory effect on the conscious experience of the hallucination. While a fourth speculative factor of a positive feedback loop is introduced to account for a number of otherwise incompatible observations. Each of the four factors in the hypothetical model is defined as precisely as is possible at present and discussed in relation to other research findings in this area and to the literature more generally. An attempt is made to spell out some of the theoretical predictions and clinical implications of the model.     

ABC法等五种免疫学方法诊断人体包虫病的比较及评价

用ABC法等五种免疫学方法可检测了101例包虫病人,40例其它病人及61例正常人抗E.g抗体。各法敏感性为,ABC为94.06％,ELISA为81.19％,IHA为87.13％,CIEP为71.29％,ID为87.50％。ID假阳性率较高(37.50％),而其余四种方法均获较高特异性(94.06～100％)。分析结果表明,初发且包虫囊完整的肺包虫病人抗体反应性最低,复发或囊破裂的病人抗体反应强且无因包虫囊肿寄生部位不同造成的抗体反应的差异。故认为:影响包虫病人特异性抗体反应的主要因素可能是包虫囊壁的屏障作用。     

Model based analysis of sleep disordered breathing in congestive heart failure

We employed a computational model of the respiratory control system to examine which of several factors, in isolation and in combination, can contribute to or explain the development of Cheyne-Stokes breathing (CSB). Our approach uses a graphical method for stability analysis similar, in concept, to the phase plane. The results from the computer simulations indicate that a postulated three-fold increase in the chemosensitivity of the central chemoreflex (CCR) loop may, by itself, explain development of CSB. By contrast, a similar increase in the chemosensitivity of the peripheral chemoreflex (PCR) loop cannot, by itself, account for CSB. The analysis reveals that the system is more readily destabilized by increasing the gain of only one chemoreflex loop than by a combined increase in gain of both loops. Reduction in the cardiac output or cardiomegaly decreases the size of the stability region. We conclude that development of CSB is the result of a complex interaction between CCR and PCR loops which may, in turn, interact with decreased cardiac output and cardiomegaly.     

Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain

Two different polymorphic regions of the interleukin-6 (IL-6) gene were investigated in patients with Alzheimer's disease (AD) and non-demented controls. The -174 C allele in the promoter region of IL-6 gene was over-represented in AD patients compared to controls and significantly increased the risk of AD. Moreover, the -174 CC genotype was associated with a high risk of the disease in women. The D allele of a variable number of tandem repeat (VNTR) was in strong linkage disequilibrium with the -174 C allele and slightly increased AD risk. On the other hand, the frequency of the VNTR C allele was decreased in patients with AD and was negatively associated with the risk of developing AD. Both the -174 CC and VNTR DD genotypes were also associated with increased IL-6 levels in the blood and brain from AD. These findings suggest that IL-6 may play a multifaceted role in AD by affecting the turnover of the cytokine.     

Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains.

A viral aetiology has long been suspected for Alzheimer's disease (AD) but until now, techniques have not been sufficiently sensitive to provide clear evidence for or against the presence of any viral genome in AD brain. We have used the very highly sensitive method of polymerase chain reaction to look for herpes simplex virus type 1 (HSV1) DNA, specifically the viral thymidine kinase (TK) gene, in autopsy brain specimens. DNA-samples from HSV-infected and uninfected Vero cells have been examined concurrently to provide standard "HSV-positive" and "HSV-negative" samples, the latter guarding also against false positives caused by cross-contamination. To preclude false negatives, we have checked the presence of the human gene, hypoxanthine phosphoribosyl transferase. In all specimens from 8 AD patients and 6 normal individuals (temporal, frontal and hippocampal), we have found viral TK sequences. In contrast, in preliminary studies on lymphocytes from normals and AD patients, we did not find TK sequences. It is postulated that factors such as number or expression of viral genes and host susceptibility might be related to incidence of AD.     

Performance of normal adults on the Luria-Nebraska Neuropsychological Battery, form I.

To examine three problems in the interpretation of the Luria-Nebraska Neuropsychological Battery (LNNB), the normal participants from four different studies were pooled to form a sample of 241 LNNB profiles. The first problem addressed was the LNNB's false positive rate. All five yes/no decision rules were applied simultaneously. Each individual rule had a 0% to 8% false positive rate: combining the rules in four different ways increased the false positive rate by 0% to 6%. When divided into over and under 65 years old groups, each rule applied to the younger group had a 0% to 5% false positive rate: combining them increased the rate to 6-8%. When applying the rules to the older group, each rule had a 0 to 27% false positive rate: combining all rules but the one with the highest error rate produced a false positive rate of 27%. The false positive rate for the entire sample was 12%. To solve the second problem of interpretation, making qualitative item analyses easier, the difficulty level (i.e., percentage of normals missing the item) for each item was calculated. The third problem was the LNNB's malingering formula's accuracy. The formula was applied to the sample: as expected, the normal profiles had an inaccuracy rate of 26%. The few mildly impaired profiles had a 6% inaccuracy rate. When applied to the entire sample of normals and using the appropriate interpretive guidelines, the formula had a false positive rate of 1%.     

Herpes virus in Alzheimer's disease: relation to progression of the disease

Studies regarding different viruses of the herpes family, such as cytomegalovirus (CMV), Epstein–Barr virus (EBV), or human herpes virus 6 (HHV-6) in Alzheimer's disease (AD) are scarce. DNA from peripheral blood leukocytes (PBL) and brain samples were analyzed for the presence of CMV, EBV, or HHV-6. All samples were negative for CMV. EBV positivity was 6% in AD brains, whereas 45% of PBL samples from AD patients and 31% from controls were positive for EBV (p = 0.05). HHV-6 showed a 23% positivity in PBL samples from AD and 4% from controls (p = 0.002). 17% of AD brains were HHV-6 positive. Within a group of elderly individuals, followed up for 5 years, EBV-positive or HHV-6–positive PBL increased in those who developed clinical AD. Virus serological positivity was also investigated, and IgG levels for CMV and EBV antigens were also increased in those subjects who developed AD during the follow-up. Our findings suggest that EBV and HHV-6 may be environmental risk factors for cognitive deterioration and progression to AD in elderly persons.