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PubMed1995

DNA fingerprinting by hybridisation to oligonucleotide arrays.

Most methods for analysing variation in DNA sequences rely on gel electrophoresis, a method which is difficult to automate and to quantify. Hybridisation to oligonucleotides bound to a solid surface offers alternatives, with the advantage that they can be more readily automated and lend themselves to powerful statistical analytical procedures. In this paper, we discuss a number of different ways in which oligonucleotide arrays could be used for DNA typing for applications in forensic science.

Animals↗
PubMed1995

Statistical design and analysis of mutation studies in transgenic mice.

We have been working on identifying sources of variability in data from transgenic mouse mutation assays in order to develop appropriate statistical methods and designs for routine studies. Data from our lab and elsewhere point to the presence of significant animal-to-animal variability, which must be taken into account in statistical hypothesis tests. Here, the usual Cochran-Armitage (CA) test for trend in mutant frequencies, which takes the transgene as the experimental unit, and a generalized Cochran-Armitage test (GCA), which takes the animal as the experimental unit, are contrasted in computer simulations that help to quantify the differences between these statistical tests. The simulations report the statistical power of each test to detect treatment group differences, and their type I error rates. We find in general that the GCA test performs poorly compared to the CA test when it is appropriate to take the transgene as the experimental unit, and the study also uses a small number of animals. However, the CA test performs poorly in small group-size studies when the animal is the appropriate experimental unit. Extensions of the computer simulations allow for identification of cost-effective experimental designs. The results emphasize that the benefits of using additional animals in these mutation studies can be realized without substantial increases in costs. Here we illustrate the methods for liver studies in our lab. These methods can be used to derive optimal experimental designs for any combination of spontaneous mutant frequency and animal-to-animal variability.

Animals↗
PubMed1987

Tests of linkage and heterogeneity in Mendelian diseases using identity by descent scores.

When linkage between a recessive Mendelian disease and specific candidate genes is investigated, identity by descent scores in affected sib pairs may be used for tests of linkage and heterogeneity. Statistical tests for performing this analysis are presented. The efficiency and statistical power of the method are also investigated using computer simulations.

Biometry↗
PubMed2004

The role of haplotypes in candidate gene studies.

Human geneticists working on systems for which it is possible to make a strong case for a set of candidate genes face the problem of whether it is necessary to consider the variation in those genes as phased haplotypes, or whether the one-SNP-at-a-time approach might perform as well. There are three reasons why the phased haplotype route should be an improvement. First, the protein products of the candidate genes occur in polypeptide chains whose folding and other properties may depend on particular combinations of amino acids. Second, population genetic principles show us that variation in populations is inherently structured into haplotypes. Third, the statistical power of association tests with phased data is likely to be improved because of the reduction in dimension. However, in reality it takes a great deal of extra work to obtain valid haplotype phase information, and inferred phase information may simply compound the errors. In addition, if the causal connection between SNPs and a phenotype is truly driven by just a single SNP, then the haplotype-based approach may perform worse than the one-SNP-at-a-time approach. Here we examine some of the factors that affect haplotype patterns in genes, how haplotypes may be inferred, and how haplotypes have been useful in the context of testing association between candidate genes and complex traits.

Genetic Predisposition to Disease↗
PubMed2003

Effects of reminiscence and life review on late-life depression: a meta-analysis.

AIM: To assess the effectiveness of reminiscence and life review on late-life depression across different target groups and treatment modalities. METHOD: Twenty controlled outcome studies were retrieved from Psychlit, Medline and Dissertation Abstracts. For each study a standardised effect size, d, was calculated and a random-effects meta-analysis was conducted. RESULTS: An overall effect size of 0.84 (95% Confidence Intervals (CI)=0.31-1.37) was found, indicating a statistically and clinically significant effect of reminiscence and life review on depressive symptomatology in elderly people. This effect is comparable to the effects commonly found for pharmacotherapy and psychological treatments. The effect was larger in subjects with elevated depressive symptomatology (d=1.23) as compared to other subjects (d=0.37). Other characteristics of the subjects or interventions were not found to be related to increased or decreased effect sizes. DISCUSSION: Reminiscence and life review are potentially effective treatments for depressive symptoms in the elderly and may thus offer a valuable alternative to psychotherapy or pharmacotherapy. Especially in non-institutionalised elderly people-who often have untreated depression-it may prove to be an effective, safe and acceptable form of treatment. Randomized trials with sufficient statistical power are necessary to confirm the results of this study.

Aged↗
PubMed2003

Attenuation of brain BOLD response following lipid ingestion.

A great deal of heterogeneity exists in fMRI data. Even within the same subject, results on successive days or scan sessions often differ in the number of significantly activated pixels and/or the intensity of activation. We sought to assess whether controllable physiologic modulators, such as dietary factors, could influence the outcome of fMRI data. A high fat diet, for example, prior to a fMRI scan could change microvascular blood rheologic factors and potentially alter brain blood oxygen-level dependent (BOLD) signal patterns. In healthy adult volunteers, we measured brain BOLD signal during bilateral finger tapping (2 Hz) in the fasted state, and at 40 and 100 minutes post-ingestion of a 235 mL can of Ensure Plus (Ross Labs), alone or supplemented with either 25 cc or 50 cc of canola oil. Both the 25 cc and 50 cc Canola oil treatments produced a significant bilateral decrease in BOLD signal 40 and 100 minutes postprandial. No significant effect was observed with Ensure in the absence of oil. Therefore, to decrease fMRI within and between subject heterogeneity, and thereby increase fMRI statistical power, it is suggested that scanning within 2 hours post high fat ingestion should be avoided. As a corollary, a thorough understanding of a subject's physiological state, prior to an fMRI exam, may reduce the impact of other confounding variables.

Adult↗
PubMed2003

Early stage Parkinson's disease patients and normal volunteers: comparative mechanisms of sequence learning.

Early-stage nondemented Parkinson's disease (PD(es)) patients can learn short but not long sequences as well as controls. We have previously shown that to achieve normal performance, PD(es) patients activated the same right-sided cortical regions as controls plus the homologous left sided cortex and bilateral cerebellum. In this study, we evaluated two related hypotheses to explain the behavioral abnormalities and the increased bilateral brain activation observed in the PD(es) group. Hypothesis 1 proposed that PD(es) patients recruit regions from a normal bilateral network specialized for sequence learning that healthy controls would activate if performing difficult tasks. Thus, PD(es) patients can learn short sequences as well as controls. Hypothesis 2 proposed that information processing within the network in the PD(es) group is impaired. Thus, PD(es) patients cannot learn as difficult a sequence as controls. To test hypothesis 1, we increased task difficulty and statistical power in the control group and showed that the control and the PD(es) groups activated the same regions. To test hypothesis 2, we analyzed the equal performance data using two partial least squares (PLS) multivariate analyses. The task-PLS analysis showed that to perform equally with controls, the PD(es) group expressed the normal bilateral network more than the control group. The behavior-PLS analysis showed that the correlation between learning performance and regional activation was significantly different between the groups. We conclude that PD(es) patients have near normal learning if task difficulty is moderate because they can recruit additional regions from a normal bilateral network specialized for sequence learning. However, when a difficult task would normally require bilateral activation, PD(es) patients fail to learn because information processing within the network is impaired. Hum. Brain Mapp. 20:246-258, 2003.

Aged↗
PubMed2004

Reliability of brain volumes from multicenter MRI acquisition: a calibration study.

Multicenter studies can provide additional information over single center studies because of their increased statistical power. Because similar acquisition protocols are being used internationally for structural magnetic resonance imaging (MRI) studies of the human brain, volumetric MRI data studies seem suitable for this purpose. Possible systematic differences between sites should be avoided, however, particularly when subtle differences in tissue volume are being searched for, such as in neuropsychiatric diseases. In this calibration study, the brains of six healthy volunteers were (re)scanned with MR scanners from four different manufacturers at five different sites, using the local acquisition protocols. The images were segmented at a central reference site. The intraclass correlation coefficient (ICC) was determined for the whole brain, gray and white matter, cerebellum, and lateral and third ventricle volumes. When required, the processing algorithms were calibrated for each site. Calibration of the histogram analysis was needed for segmentation of total brain volume at one site and for gray and white matter volume at all sites. No (additional) calibration was needed for cerebellum and ventricle volumes. The ICCs were > or = 0.96 for total brain, > or = 0.92 for cerebellum, > or = 0.96 for lateral ventricle, > or = 0.21 for third ventricle, > or = 0.84 for gray matter, and > or = 0.78 for white matter volume. Calibration of segmentation procedures allows morphologic MRI data acquired at different research sites to be combined reliably in multicenter studies.

Adult↗
PubMed2007

Event-related functional near-infrared spectroscopy (fNIRS) based on craniocerebral correlations: reproducibility of activation?

The purpose of the present study was to assess the retest reliability of cortical activation detected by event-related functional near-infrared spectroscopy (fNIRS) based on craniocerebral correlations. Isolated functional activation was evoked in the motor cortex by a periodically performed finger-tapping task. During 44-channel fNIRS recording, 12 subjects performed 30 trials of right and left index finger tapping in two sessions. The retest interval was set to 3 weeks. Simple correlations of the contrast t-values supplemented by scatterplots, channel-wise intraclass correlation coefficients (ICC), as well as reproducibility indices for the size and the location of the detected activation were calculated. The results at the group level showed sufficient single measure ICCs (up to 0.80) and excellent reproducibility of the size and the location (up to 89% were reproducible). Comparisons of the intersession group amplitudes demonstrate that the fNIRS signals were stable across time in a retest study design: the number of significant differences was less than randomly occurring false-positive activated channels if an alpha level of 5% is chosen. Effect size analyses indicated that the intersession amplitude differences are small (mean < 0.25). For deoxyhemoglobin and oxyhemoglobin distinct statistical power profiles were revealed regarding the activation vs. baseline contrast as well as the intersession amplitude differences, indicating a higher sensitivity of deoxyhemoglobin for local hemodynamic changes. The results suggest that sensorimotor activation assessed by event-related fNIRS based on craniocerebral correlations is sufficiently reproducible at the group level.

Adult↗
PubMed2000

Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival.

Median survival time of nonresectable hilar bile duct cancer is only 4 to 6 months owing to tumor spread in the biliary tree, refractory cholestasis, and sepsis or liver failure. We explored whether local photodynamic therapy of nonresectable bile duct cancer could improve survival. A sample size of 23 patients is required to detect an increase in 6-month survival rate from less than 50% to greater than 70% in a single-arm phase-II trial with a statistical power of 80% (Fleming's single step procedure; alpha = 0.05). Twenty-three consecutive patients (8 women, 15 men; 67 +/- 14 years) with nonresectable bile duct cancer (Bismuth type III n = 2, type IV n = 21) were treated with photodynamic therapy and biliary endoprosthesis. Photofrin (QLT Pharmaceuticals, Vancouver, Canada) (2 mg/kg body weight intravenously) was photoactivated after 1 to 4 days with laser light (630 nm; 242 J/cm(2)) via endoscopic retrograde access. The 6-month survival rate was 91% after diagnosis and 74% after start of photodynamic therapy (30-day mortality rate was 4%) at a median follow-up time of 10.3 months after diagnosis. Causes of death were tumor progression (n = 9) and bacterial infections (n = 4). The median rate of local tumor response was 74%, 54%, 29%, and 67% after the first, second, third, fourth, and fifth photodynamic therapy. Time to progression ranged from 3 to 8 months. All patients, except 1 with diffuse liver metastases, improved in cholestasis, performance, and quality of life. Photodynamic therapy can prevent tumor occlusion of hilar bile ducts. The apparent benefit in survival time should be confirmed in a controlled trial versus palliation by endoprosthesis only.

Adenocarcinoma↗
PubMed2002

Sources of variability in genetic association studies: insights from the analysis of hepatic lipase (LIPC).

Genetic association studies have been widely used to identify loci that influence plasma lipoprotein concentrations, but few of the associations reported have proved consistently reproducible across different study populations. This lack of consistency is a widely recognized limitation of association studies, and is often ascribed to inadequate statistical power, population substructure, and population-specific linkage disequilibrium. However, few studies have assessed the causes of variability underlying a given genotype-phenotype association. We have examined two possible sources of variability in the association between the -514 polymorphism in hepatic lipase (LIPC) and plasma HDL-C concentrations. First, we compared the association between this polymorphism and hepatic lipase activity in four populations. A single copy of the -514C allele was associated with a 10 mmol.hr(-1).l(-1) increase in hepatic lipase activity in white American and Turkish men but only approximately 5 mmol.hr(-1).l(-1) in Chinese and African-American men. Second, we tested the effects of a stanozolol-induced increase in hepatic lipase activity on plasma HDL-C concentrations in men with normal (< 150mg/dl) or elevated (150-300mg/dl) levels of plasma triglyceride. The increase in hepatic lipase activity was similar in the two groups, but the resulting decline in HDL-C levels was significantly greater in normolipidemic men. These data suggest that the effect of a polymorphism on gene expression can vary among individuals, and that the resulting phenotype may be further modified by interactions with other factors. Three novel LIPC polymorphisms were identified in the study (-1596insC, -2740A>G, and -2880G>C).

Adult↗
PubMed2005

Reproductive and hormonal factors and risk of brain tumors in adult females.

Causes of brain tumors are largely unknown, and there is an urgent need to identify possible risk factors. Several observations point to a possible role of reproductive hormones, but few epidemiologic studies have examined whether reproductive factors, such as age at menarche and parity, are associated with brain tumor risk. We conducted a multi-center case-control study of newly diagnosed glioma (n = 212) and meningioma (n = 151) and frequency-matched controls (n = 436) in women from hospitals in Phoenix, Arizona; Boston, Massachusetts; and Pittsburgh, Pennsylvania between 1994 and 1998. Research nurses interviewed patients regarding potential risk factors for brain tumors, including reproductive factors and hormone use. Unconditional logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Risk of glioma increased with older age at menarche [OR = 1.90 (95% CI = 1.09-3.32) for age at menarche > or =14 vs. <12 years]. Early age at first birth was associated with reduced risk of glioma [OR = 0.43 (95% CI = 0.23-0.83) for a first birth before age 20 vs. nulliparity], but there was little effect of number of births. Exogenous hormone use was also associated with a lower risk of glioma, but risks did not vary systematically according to duration of use or age at first use. Possibly owing to low statistical power, there were few noteworthy associations between meningioma and reproductive factors, other than a nonsignificant (p = 0.09) trend of increasing risk with increasing age at menopause. The findings suggest that hormonal exposures early in life may be associated with risk of glioma, but the evidence is inconsistent and does not point clearly to a specific causal or protective hypothesis.

Adolescent↗
PubMed2006

A prospective study of breast size and premenopausal breast cancer incidence.

Studies of the association between breast size, as a proxy for mammary gland mass, and breast cancer risk have given equivocal results. Most have been case-control studies with limited statistical power. We conducted a prospective analysis of the relation between breast size as measured by self-reported bra cup size and breast cancer risk among premenopausal women enrolled in the Nurses' Health Study II. Bra cup size at age 20 was assessed among 89,268 premenopausal women aged 29-47 in 1993. Subsequent incident cases of invasive breast cancer were assessed until 2001. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with a Cox proportional hazards model adjusting for potential confounders and risk factors for breast cancer. During 622,732 person-years of follow-up, 803 premenopausal women were newly diagnosed with invasive breast cancer. For women with a BMI below 25 kg/m2, those with a bra cup size of "D or larger" had a significantly higher incidence of breast cancer than women who reported "A or smaller" (covariate adjusted HR=1.80; 95% CI 1.13-2.88; ptrend=0.01). There was no significant association among women with a BMI of 25 kg/m2 or higher. Stratifying by BMI at age 18 at a cutoff point of 21 kg/m2 gave similar results. Larger bra cup size at a young age is associated with a higher incidence of premenopausal breast cancer, though this association is limited to leaner women.

Adult↗
PubMed2007

CENP-F expression is associated with poor prognosis and chromosomal instability in patients with primary breast cancer.

DNA microarrays have the potential to classify tumors according to their transcriptome. Tissue microarrays (TMAs) facilitate the validation of biomarkers by offering a high-throughput approach to sample analysis. We reanalyzed a high profile breast cancer DNA microarray dataset containing 96 tumor samples using a powerful statistical approach, between group analyses. Among the genes we identified was centromere protein-F (CENP-F), a gene associated with poor prognosis. In a published follow-up breast cancer DNA microarray study, comprising 295 tumour samples, we found that CENP-F upregulation was significantly associated with worse overall survival (p<0.001) and reduced metastasis-free survival (p<0.001). To validate and expand upon these findings, we used 2 independent breast cancer patient cohorts represented on TMAs. CENP-F protein expression was evaluated by immunohistochemistry in 91 primary breast cancer samples from cohort I and 289 samples from cohort II. CENP-F correlated with markers of aggressive tumor behavior including ER negativity and high tumor grade. In cohort I, CENP-F was significantly associated with markers of CIN including cyclin E, increased telomerase activity, c-Myc amplification and aneuploidy. In cohort II, CENP-F correlated with VEGFR2, phosphorylated Ets-2 and Ki67, and in multivariate analysis, was an independent predictor of worse breast cancer-specific survival (p=0.036) and overall survival (p=0.040). In conclusion, we identified CENP-F as a biomarker associated with poor outcome in breast cancer and showed several novel associations of biological significance.

Adult↗
PubMed2007

Prediction of metastasis from low-malignant breast cancer by gene expression profiling.

Promising results for prediction of outcome in breast cancer have been obtained by genome wide gene expression profiling. Some studies have suggested that an extensive overtreatment of breast cancer patients might be reduced by risk assessment with gene expression profiling. A patient group hardly examined in these studies is the low-risk patients for whom outcome is very difficult to predict with currently used methods. These patients do not receive adjuvant treatment according to the guidelines of the Danish Breast Cancer Cooperative Group (DBCG). In this study, 26 tumors from low-risk patients were examined with gene expression profiling. An intermediate risk group of 34 low-malignant T2 tumors that fulfilled all other low-risk criteria than tumor size was included to increase statistical power. A 32-gene classifier, HUMAC32, was identified and it predicted metastases with 80% sensitivity and 77% specificity. The classifier was also validated in an independent group of high-risk tumors resulting in comparable performance of HUMAC32 and a 70-gene classifier developed for this group. Furthermore, the 70-gene signature was tested in our low- and intermediate-risk samples. The results demonstrated high cross-platform consistency of the classifiers. Higher performance of HUMAC32 was demonstrated among the low-malignant cancers compared with the 70-gene classifier. This suggests that although the metastatic potential to some extend is determined by the same genes in groups of tumors with different characteristics and risk, expression-based classification specifically developed in low-risk patients have higher predictive power in this group.

Biomarkers, Tumor↗
PubMed1996

Effects of a personal trainer and financial incentives on exercise adherence in overweight women in a behavioral weight loss program.

Exercise is important for long-term weight loss, but few studies have examined ways to improve exercise adherence in overweight subjects participating in a behavioral weight loss program. This paper presents two studies, one conducted at the University of Pittsburgh and one at the University of Minnesota, that sought to improve exercise adherence by exerting more direct control over the environmental antecedents and consequences controlling exercise. Study 1 investigated the use of a personal trainer who called participants regularly and met them at their home or office at scheduled times for a walk. Study 2 investigated the effect of a lottery incentive for exercise adherence. In both studies, the effect of these manipulations was examined in the context of a 24-week standard behavioral weight control program with three supervised exercise sessions per week. Neither intervention achieved statistically significant improvements in exercise adherence compared to control conditions, perhaps due in part to the limited statistical power of the studies. Future studies should focus on better understanding the barriers to exercise and designing behavioral interventions that address these barriers.

Adult↗
PubMed1991

Lack of effect of a high-fat meal on the volume of distribution of theophylline in humans.

The pharmacokinetics of intravenously administered theophylline were studied in five healthy nonsmokers. Each subject received 5 mg/kg of theophylline as aminophylline after an overnight fast and again after a standard high-fat meal. Although there was wide between-day variation in the elimination rate constant in three of the five subjects, no statistically significant differences were observed in area under the time-versus-concentration curve, maximum serum theophylline concentration, elimination rate constant, or apparent volume of distribution between the two treatments. A statistical power analysis indicated that if differences in volume of distribution and maximum serum theophylline concentration occur in the general population, the mean differences are less less than 15% and 20%, respectively. This suggests that alterations in intravascular drug distribution resulting from eating a high-fat meal do not contribute importantly to previously reported effects of food on serum theophylline concentrations after oral dosing.

Adult↗
PubMed1993

Bioavailability studies of drugs with nonlinear pharmacokinetics: II. Absolute bioavailability of intravenous phenytoin prodrug at therapeutic phenytoin serum concentrations determined by double-stable isotope technique.

Measurement of the absolute bioavailability of phenytoin (PHT) derived from test doses of phenytoin prodrug (PPD) at therapeutic PHT serum concentrations is complicated by two problems: 1) the area under the serum concentration versus time curve (AUC) produced by a given size of test dose will vary directly with background PHT serum concentration due to the nonlinear pharmacokinetic properties of PHT; 2) PPD is more water soluble than PHT, making renal excretion of PPD more likely. The authors describe a double-stable isotope method that obviates these two problems. Using only six subjects, the authors were able to demonstrate bioequivalence of PHT derived from intravenous PPD with intravenous PHT by current FDA standards for AUC ratio of test/reference formulation (90% confidence intervals between 0.80 and 1.20; ratio > or = 0.80 in > or = 80% of subjects; statistical power to detect a difference of 0.20 with a probability of 0.80).

Adult↗