PubMed Health⌕ Search

Biomedical subjects

Juni Palmgren

Publications and source records attributed to Juni Palmgren.

At least 19 recordsLinked to original sources
PubMed2006

Synergy between cigarette smoking and human papillomavirus type 16 in cervical cancer in situ development.

BACKGROUND: A majority of studies have implicated the involvement of cigarette smoking in cervical cancer development, although its mechanism of action remains unclear. We conducted a large population-based case-control study to address the potential interaction between smoking and human papillomavirus type 16 (HPV-16) in development of cervical cancer in situ (CIS). METHODS: Information on risk factors for CIS was collected via interview, and archival cervical smears were tested for HPV-16 DNA presence in cases (n = 375) and controls (n = 363). Adjusted odds ratios (OR) for the effects of smoking, HPV-16 presence/absence, and load at first smear (taken, on average, 9 years before diagnosis) were calculated. RESULTS: The risk for CIS among current smokers who were HPV-16 positive at time of first smear was >14-fold [adjusted OR, 14.4; confidence interval (95% CI), 5.6-36.8] compared with HPV-16-negative current smokers. In contrast, the risk for CIS among HPV-16-positive nonsmokers was only 6-fold (adjusted OR, 5.6; 95% CI, 2.7-11.5), compared with HPV-16-negative nonsmokers. HPV-16-positive smokers with high viral load at time of first smear exhibited a high risk for CIS (adjusted OR, 27.0; 95% CI, 6.5-114.2) compared with HPV-16-negative smokers. Within nonsmokers, however, high HPV-16 load contributed only a 6-fold increased risk compared with HPV-16-negative nonsmokers (adjusted OR, 5.9; 95% CI, 2.4-14.6). Interaction was observed (P = 0.03) between duration of smoking and HPV-16 presence in CIS development. CONCLUSION: Results suggest a synergistic effect between smoking and both HPV-16 status and HPV-16 viral load, which may occur almost a decade before CIS detection.

Adolescent↗
PubMed2006

Early biochemical outcomes following permanent interstitial brachytherapy as monotherapy in 1050 patients with clinical T1-T2 prostate cancer.

BACKGROUND AND PURPOSE: Five European centres (France, Finland, Italy, Spain and the UK) have pooled data to generate a large patient series involving 1175 patients treated with prostate brachytherapy. This paper reports preliminary data on PSA outcome up to 4 years. PATIENTS AND METHODS: Out of 1175 in the database, 1050 patients with localised prostate cancer who had received transperineal seed implantation as monotherapy between May 1998 and August 2003 were stage T1-T2. A total of 668 (63.6%) patients met the low-risk group definition, 297 (28.3%) as intermediate-risk definition and 66 (6.3%) the high-risk group definition. The majority of patients were Gleason score 6 or less (n=951) and disease stage was T1c in 557 patients. RESULTS: Of the 1050 patients, PSA data up to 4 years were available for 210 patients, while 364 patients with PSA values up to 36 months were evaluable by the Kaplan-Meier method for freedom from biochemical failure. The biochemical progression-free rate at 3 years was estimated to be 91%, with a 93% and 88% rate for low- and intermediate-risk groups, respectively, versus 80% for the high-risk group. PSA kinetics provide encouraging evidence of treatment efficacy. CONCLUSION: These data on 4-year PSA follow-up on patients treated with prostate brachytherapy reflect those previously reported in the literature. This patient series will be followed to provide long-term outcome in the future.

Aged↗
PubMed2006

Linkage disequilibrium mapping of CHEK2: common variation and breast cancer risk.

BACKGROUND: Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs). METHODS AND FINDINGS: We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population--0.7% in cases and 0.4% in controls--with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99-5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population. CONCLUSIONS: Notwithstanding the involvement of the CHEK2 gene in breast cancer aetiology, we show that common polymorphisms do not influence postmenopausal breast cancer risk.

Aged↗
PubMed2006

Likelihood ratio tests in behavioral genetics: problems and solutions.

The likelihood ratio test of nested models for family data plays an important role in the assessment of genetic and environmental influences on the variation in traits. The test is routinely based on the assumption that the test statistic follows a chi-square distribution under the null, with the number of restricted parameters as degrees of freedom. However, tests of variance components constrained to be non-negative correspond to tests of parameters on the boundary of the parameter space. In this situation the standard test procedure provides too large p-values and the use of the Akaike Information Criterion (AIC) or the Bayesian Information Criterion (BIC) for model selection is problematic. Focusing on the classical ACE twin model for univariate traits, we adapt existing theory to show that the asymptotic distribution for the likelihood ratio statistic is a mixture of chi-square distributions, and we derive the mixing probabilities. We conclude that when testing the AE or the CE model against the ACE model, the p-values obtained from using the chi(2)(1 df) as the reference distribution should be halved. When the E model is tested against the ACE model, a mixture of chi(2)(0 df), chi(2)(1 df) and chi(2)(2 df) should be used as the reference distribution, and we provide a simple formula to compute the mixing probabilities. Similar results for tests of the AE, DE and E models against the ADE model are also derived. Failing to use the appropriate reference distribution can lead to invalid conclusions.

Analysis of Variance↗
PubMed2006

Prognostic markers under watchful waiting and radical prostatectomy.

A suitable setting to analyze factors that determine prognosis or treatment response in prostate cancer is an unbiased comparison of radical prostatectomy and watchful waiting as in the Scandinavian Prostate Cancer Group Trial number 4. In our previous presentation of 10-year results, we studied Gleason score, serum prostate-specific antigen (PSA) at diagnosis, and age at diagnosis as modifiers of the effect of radical prostatectomy on survival. Because overall prognostic information obtained by these parameters or by tumor stage was not provided in our publication, we now present these data in the two study arms separately.

Biomarkers↗
PubMed2006

Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma.

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.

Adolescent↗
PubMed2006

Comprehensive analysis of the ATM, CHEK2 and ERBB2 genes in relation to breast tumour characteristics and survival: a population-based case-control and follow-up study.

BACKGROUND: Mutations in the ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2) genes and amplification of the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene have been suggested to have an important role in breast cancer aetiology. However, whether common variation in these genes has a role in the development of breast cancer or breast cancer survival in humans is still not clear. METHODS: We performed a comprehensive haplotype analysis of the ATM, CHEK2 and ERBB2 genes in a Swedish population-based study, which included 1,579 breast cancer cases and 1,516 controls. We followed the cases for 8.5 years, on average, and retrieved information on the date and cause of death during that period from the nationwide Swedish causes of death registry. We selected seven haplotype-tagging SNPs (tagSNPs) in the ATM gene, six tagSNPs in the CHEK2 gene and seven tagSNPs in the ERBB2 gene that predicted both haplotypic and single locus variations in the respective genes with R2 values > or = 0.8. These tagSNPs were genotyped in the complete set of cases and controls. We computed expected haplotype dosages of the tagSNP haplotypes and included the dosages as explanatory variables in Cox proportional hazards or logistic regression models. RESULTS: We found no association between any genetic variation in the ATM, CHEK2 or ERBB2 genes and breast cancer survival or the risk of developing tumours with certain characteristics. CONCLUSION: Our results indicate that common variants in the ATM, CHEK2 or ERBB2 genes are not involved in modifying breast cancer survival or the risk of tumour-characteristic-defined breast cancer.

Aged↗
PubMed2006

Bias in variance components due to nonresponse in twin studies.

Incomplete data on trait values may bias estimates of genetic and environmental variance components obtained from twin analyses. If the nonresponse mechanism is 'ignorable' then methods such as full information maximum likelihood estimation will produce consistent variance component estimates. If, however, nonresponse is 'nonignorable', then the situation is more complicated. We demonstrate that a within-pair correlation of nonresponse, possibly different for monozygotic (MZ) and dizygotic (DZ) twins, may well be compatible with 'ignorability'. By means of Monte Carlo simulation, we assess the potential bias in variance component estimates for different types of nonresponse mechanisms. The simulation results guide the interpretation of analyses of data on perceptual speed from the Swedish Adoption/Twin Study of Aging. The results suggest that the dramatic decrease in genetic influences on perceptual speed observed after 13 years of follow-up is not attributable solely to dropout from the study, and thus support the hypothesis that genetic influences on some cognitive abilities decrease with age in late life.

Aging↗
PubMed2005

Analysis of binary traits: testing association in the presence of linkage.

Most methods for testing association in the presence of linkage, using family-based studies, have been developed for continuous traits. FBAT (family-based association tests) is one of few methods appropriate for discrete outcomes. In this article we describe a new test of association in the presence of linkage for binary traits. We use a gamma random effects model in which association and linkage are modelled as fixed effects and random effects, respectively. We have compared the gamma random effects model to an FBAT and a generalized estimating equation-based alternative, using two regions in the Genetic Analysis Workshop 14 simulated data. One of these regions contained haplotypes associated with disease, and the other did not.

Genetic Linkage↗
PubMed2005

Radical prostatectomy versus watchful waiting in early prostate cancer.

BACKGROUND: In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results. METHODS: From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression. RESULTS: During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test). CONCLUSIONS: Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.

Aged↗
PubMed2005

Does prenatal sonography affect intellectual performance?

BACKGROUND: Little is known about potential risks of ultrasound during pregnancy. The developing brain is susceptible to environmental influences, and prenatal ultrasound has been reported to affect cognitive abilities in animals. METHODS: To assess a possible association between prenatal ultrasound and intellectual performance, we studied men born in Sweden from 1973 to 1978 who enrolled for military service from 1991 to 1996. Intellectual scores (mean +/- standard deviation = 5 +/- 2) were measured by a test battery at enrollment, and subnormal performance was defined as a score of 3 or less. We estimated differences in mean intellectual score between ultrasound-exposed and ultrasound-unexposed using linear regression, and we calculated relative risks of subnormal performance using logistic regression analysis. RESULTS: There were 7999 eligible men born in a hospital (Malmo) that included ultrasound scanning in standard antenatal care (exposed) and 197,829 men born in hospitals without ultrasound scanning programs (unexposed). We found lower intellectual performance scores (mean difference = -0.16; 95% confidence interval = -0.21 to -0.11) and an increased risk of subnormal performance (odds ratio = 1.28; CI = 1.18 to 1.38) among ultrasound-exposed compared with unexposed. However, men born in Malmo before scanning was introduced also had lower scores, and the decrease in test scores after the introduction of ultrasound was small. Moreover, we found no differences in intellectual performance within pairs of brothers as a result of ultrasound exposure. CONCLUSIONS: This study failed to demonstrate a clear association between ultrasound scanning and intellectual performance.

Adolescent↗
PubMed2004

Common variants of ACE contribute to variable age-at-onset of Alzheimer's disease.

Studies on the role that genetic variation may play in a complex human disease can be empowered by an assessment of both disease risk in case-control or family models and of quantitative traits that reflect elements of disease etiology. An excellent example of this can be found for the epsilon4 allele of APOE in relation to Alzheimer's disease (AD) for which association with both risk and age-at-onset (AAO) is evident. Following a recent demonstration that variants of the gene encoding angiotensin I converting enzyme ( ACE) contribute to AD risk, we have explored the potential influence of ACE upon AAO in AD. A total of 2861 individuals from three European populations, including six independent AD samples, have been examined in this study. Three single nucleotide polymorphisms (SNPs) previously demonstrated to have maximum effects upon ACE plasma levels and that span the ACE locus were genotyped in these materials. A strong effect upon AAO was observed for marker rs4343 in exon 17 ( P<0.0001), but evidence was also obtained indicating a possible independent effect of marker rs4291 ( P=0.0095) located in the ACE promoter. Effects were consistent with data from previous studies suggesting association with AD in case-control models, whereby alleles demonstrated to confer risk to disease also appear to reduce AAO. Equivalent effects were evident regardless of APOE epsilon4 carrier status and in both males and females. These results provide an important complement to existing AD risk data, confirming that ACE harbors sequence variants that contribute to aspects of AD pathology.

Age of Onset↗
PubMed2004

Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism.

Linkage studies have provided evidence that one or more loci on chromosome 9q influence Alzheimer disease (AD). The gene encoding the ATP-binding cassette A1 transporter (ABCA1) resides within proximity of previously identified linkage peaks and represents a plausible biological candidate for AD due to its central role in cellular lipid homeostasis. Several single nucleotide polymorphisms (SNPs) spanning ABCA1 have been genotyped and haplotype-based association analyses performed in four independent case-control samples, consisting of over 1,750 individuals from three European populations representing both early and late-onset AD. Prominent effects were observed for a common (H2) and rarer haplotype (H5) that were enriched in AD cases across studied populations (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.36-1.82; P<0.00001 and OR 2.90; 95% CI 2.54-3.27; P<0.00001, respectively). Two other common haplotypes in the studied region (H1 and H3) were significantly under-represented in AD cases, suggesting that they may harbor alleles that decrease disease risk (OR 0.79, 95% CI 0.64-0.94; P=0.0065 and OR 0.70, 95% CI 0.46-0.93; P=0.011, respectively). While findings were significant in both early and late-onset samples, haplotype effects were more distinct in early-onset materials. For late-onset samples, ancillary evidence was obtained that both single marker alleles and haplotypes of ABCA1 contribute to variable cerebrospinal fluid tau and beta amyloid (Abeta42) protein levels, and brain Abeta load. Results indicate that variants of ABCA1 may affect the risk of AD, providing further support for a genetic link between AD and cholesterol metabolism.

ATP Binding Cassette Transporter 1↗
PubMed2003

Three-state frailty model for age at onset of dementia and death in Swedish twins.

We present a frailty model to estimate the relative importance of genetic and environmental factors on age at onset of dementia in a twin design. We use modern survival methodology to define a model that accounts simultaneously for longitudinal aspects, e.g., left truncation and right censoring in data, and the multivariate nature of twin data. Additionally, we present a novel three-state frailty model, with nondemented, demented, and dead states, describing variation in the onset of disease and mortality simultaneously in one model, while accounting for possible dependence for the two competing events. The frailty structure, i.e., the latent random effects structure, mimics the traditional twin model for continuous variables used in quantitative genetics, and as such describes within-pair dependence. This in turn leads to estimates for intrapair correlations, as well as for additive genetic, and shared and nonshared environmental components of variance. A hierarchical Bayesian model formulation and Gibbs sampling are used to estimate posterior distributions of the parameters. The models are applied to Swedish Twin Registry data on the onset of dementia in elderly twins. Based on the three-state frailty model, we estimate the intrapair correlations for dementia to be 0.87 [90% credible interval: 0.61,0.98] and 0.68[0.18,0.91] for MZ and DZ twins, respectively. Based on our model, we estimate that genetic effects account for about one third, and shared environmental effects for almost a half, of the variation in dementia hazards between individuals. More data, however, are needed to gain precision in these estimates.

Age of Onset↗
PubMed2003

The influence of mortality on twin models of change: addressing missingness through multiple imputation.

Twin analyses of phenotypes that are associated with mortality may provide biased heritability estimates if the models require that data from both members of a pair are available. This is particularly true when longitudinal analyses are applied to measures of cognition or biomarkers of aging. The effect of applying imputational techniques that include information on age at death was tested on longitudinal data from two twin studies of aging, each with up to four occasions of measurement. Measures of twin similarity for intercepts and slopes from three latent growth curve models were compared: without imputed data, including imputed data but without information on age at death, and including imputed data with information on age at death. Results indicated that twin similarity for slopes decreases when mortality is accounted for, but that considerable age-related covariation remains.

Humans↗
PubMed2002

A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer.

BACKGROUND: Radical prostatectomy is widely used in the treatment of early prostate cancer. The possible survival benefit of this treatment, however, is unclear. We conducted a randomized trial to address this question. METHODS: From October 1989 through February 1999, 695 men with newly diagnosed prostate cancer in International Union against Cancer clinical stage T1b, T1c, or T2 were randomly assigned to watchful waiting or radical prostatectomy. We achieved complete follow-up through the year 2000 with blinded evaluation of causes of death. The primary end point was death due to prostate cancer, and the secondary end points were overall mortality, metastasis-free survival, and local progression. RESULTS: During a median of 6.2 years of follow-up, 62 men in the watchful-waiting group and 53 in the radical-prostatectomy group died (P=0.31). Death due to prostate cancer occurred in 31 of 348 of those assigned to watchful waiting (8.9 percent) and in 16 of 347 of those assigned to radical prostatectomy (4.6 percent) (relative hazard, 0.50; 95 percent confidence interval, 0.27 to 0.91; P=0.02). Death due to other causes occurred in 31 of 348 men in the watchful-waiting group (8.9 percent) and in 37 of 347 men in the radical-prostatectomy group (10.6 percent). The men assigned to surgery had a lower relative risk of distant metastases than the men assigned to watchful waiting (relative hazard, 0.63; 95 percent confidence interval, 0.41 to 0.96). CONCLUSIONS: In this randomized trial, radical prostatectomy significantly reduced disease-specific mortality, but there was no significant difference between surgery and watchful waiting in terms of overall survival.

Aged↗
PubMed2002

Maximum likelihood inference for multivariate frailty models using an automated Monte Carlo EM algorithm.

We present a maximum likelihood estimation procedure for the multivariate frailty model. The estimation is based on a Monte Carlo EM algorithm. The expectation step is approximated by averaging over random samples drawn from the posterior distribution of the frailties using rejection sampling. The maximization step reduces to a standard partial likelihood maximization. We also propose a simple rule based on the relative change in the parameter estimates to decide on sample size in each iteration and a stopping time for the algorithm. An important new concept is acquiring absolute convergence of the algorithm through sample size determination and an efficient sampling technique. The method is illustrated using a rat carcinogenesis dataset and data on vase lifetimes of cut roses. The estimation results are compared with approximate inference based on penalized partial likelihood using these two examples. Unlike the penalized partial likelihood estimation, the proposed full maximum likelihood estimation method accounts for all the uncertainty while estimating standard errors for the parameters.

Algorithms↗