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1.  PROSPECTIVE STUDY OF HPV16 VIRAL LOAD AND RISK OF IN SITU AND INVASIVE SQUAMOUS CERVICAL CANCER 
Background
A strong association has been shown between high viral DNA load (VL) of human papillomavirus (HPV) type 16 and risk for cervical cancer in situ (CIS). However, little data is available for the significance of VL in invasive squamous cell carcinoma (SCC).
Methods
In two nested case-control studies among women participating in cervical screening, with a cytologically normal first smear, we collected 5665 smears from 621 women with CIS, 457 with SCC, and individually matched controls. All smears were tested for HPV, and VLs of HPV16 positive smears were quantified using realtime-PCR. The median follow-up until diagnosis of CIS or SCC was 6.1-7.7 years.
Results
Low VL’s were common among both CIS and SCC case women, until 1-2 years before diagnosis when a surge in VL occurred. The relative risk (RR) associated with low viral load of HPV16 was around 10 for CIS, and 10-20 for SCC throughout 10 years before diagnosis, compared to HPV16-negative women. For women with medium to high VL, the risk for CIS was greatly increased from five years before diagnosis (RR=19, 95% confidence interval 7-48). In SCC, a high VL conferred an increased risk, but only from 3 years before diagnosis (RR=60, 95% CI 6-580).
Conclusions
We demonstrate differing risk functions associated with HPV16 viral load in CIS and SCC, respectively. We further show that viral loads were unexpectedly low early in the SCC disease process.
Impact
HPV16 viral load appears highly complex which may limit its use in cervical screening.
doi:10.1158/1055-9965.EPI-12-0953-T
PMCID: PMC3538961  PMID: 23155137
Cervical cancer; HPV; HPV16; viral load; sensitivity
2.  Results From the Scandinavian Prostate Cancer Group Trial Number 4: A Randomized Controlled Trial of Radical Prostatectomy Versus Watchful Waiting 
In the Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4), 347 men were randomly assigned to radical prostatectomy and 348 to watchful waiting. In the most recent analysis (median follow-up time = 12.8 years), the cumulative mortality curves had been stable over the follow-up. At 15 years, the absolute risk reduction of dying from prostate cancer was 6.1% following randomization to radical prostatectomy, compared with watchful waiting. Hence, 17 need to be randomized to operation to avert one death. Data on self-reported symptoms, stress from symptoms, and quality of life were collected at 4 and 12.2 years of median follow-up. These questionnaire studies show an intricate pattern of symptoms evolving after surgery, hormonal treatments, signs of tumor progression, and also from natural aging. This article discusses some of the main findings of the SPCG-4 study.
doi:10.1093/jncimonographs/lgs025
PMCID: PMC3540876  PMID: 23271778
3.  Individualized Estimation of the Benefit of Radical Prostatectomy from the Scandinavian Prostate Cancer Group Randomized Trial 
European Urology  2012;62(2):204-209.
Background
Although there is randomized evidence that radical prostatectomy improves survival, there are few data on how benefit varies by baseline risk.
Objective
We aimed to create a statistical model to calculate the decrease in risk of death associated with surgery for an individual patient, using stage, grade, prostate-specific antigen, and age as predictors.
Design, setting, and participants
A total of 695 men with T1 or T2 prostate cancer participated in the Scandinavian Prostate Cancer Group 4 trial (SPCG-4).
Intervention
Patients in SPCG-4 were randomized to radical prostatectomy or conservative management.
Outcome measurements and statistical analysis
Competing risk models were created separately for the radical prostatectomy and the watchful waiting group, with the difference between model predictions constituting the estimated benefit for an individual patient.
Results and limitations
Individualized predictions of surgery benefit varied widely depending on age and tumor characteristics. At 65 yr of age, the absolute 10-yr risk reduction in prostate cancer mortality attributable to radical prostatectomy ranged from 4.5% to 17.2% for low- versus high-risk patients. Little expected benefit was associated with surgery much beyond age 70. Only about a quarter of men had an individualized benefit within even 50% of the mean. A limitation is that estimates from SPCG-4 have to be applied cautiously to contemporary patients.
Conclusions
Our model suggests that it is hard to justify surgery in patients with Gleason 6, T1 disease or in those patients much above 70 yr of age. Conversely, surgery seems unequivocally of benefit for patients who have Gleason 8, or Gleason 7, stage T2. For patients with Gleason 6 T2 and Gleason 7 T1, treatment is more of a judgment call, depending on patient preference and other clinical findings, such as the number of positive biopsy cores and comorbidities.
doi:10.1016/j.eururo.2012.04.024
PMCID: PMC3389180  PMID: 22541389
Prostatic neoplasms; Statistics and research design; Randomized controlled trial; Prostatectomy
4.  NordicDB: a Nordic pool and portal for genome-wide control data 
European Journal of Human Genetics  2010;18(12):1322-1326.
A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal (http://www.nordicdb.org). The current version of NordicDB pools together high-density genome-wide SNP information from ∼5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW–SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries.
doi:10.1038/ejhg.2010.112
PMCID: PMC3002853  PMID: 20664631
common controls; genome-wide data; Nordic Control Database; population stratification
5.  Prospective study of HPV types, HPV persistence and risk of squamous cell carcinoma of the cervix 
Background
The link between squamous cell cervical carcinoma and HPV 16/18 is well-established but the magnitude of the risk association is uncertain and the importance of other high-risk HPV types unclear.
Methods
In two prospective nested case-control series among women participating in cytological screening in Sweden, we collected 2772 cervical smears from 515 women with cancer in situ (CIS), 315 with invasive squamous cell carcinoma (SCC), and individually matched controls. All smears were tested for HPV with PCR assays and the median follow-up until diagnosis was 5-7 years. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI).
Results
Presence of HPV16/18 in the first smear was associated with 8.5-fold (95% CI 5.3-13.7), and 18.6-fold (95% CI 9.0-38.9) increased risks of CIS and SCC, respectively, compared to women negative for HPV. Infection with other high-risk HPV types in the first smear was also associated with significantly increased risks for both CIS and SCC. Persistence of HPV16 infection conferred a RR of 18.5 (95% CI, 6.5-52.9) for CIS and 19.5 (95% CI 4.7-81.7) for SCC. The HPV16/18 attributable risk proportion was estimated to 30-50% of CIS, and 41-47% of SCC. Other high-risk HPV types also conferred significant proportions.
Conclusions
Our large population-based study provides quantification of risks for different HPV types and prospective evidence that non-16/18 high-risk HPV types increase the risk for future cervical cancer.
Impact
This study gives further insights into cervical cancer risk stratification with implications for HPV-based prevention strategies.
doi:10.1158/1055-9965.EPI-10-0424
PMCID: PMC2952359  PMID: 20671136
Cervical cancer; HPV; risk; prevalence; persistence
6.  The Genetic Structure of the Swedish Population 
PLoS ONE  2011;6(8):e22547.
Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise Fst) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions.
doi:10.1371/journal.pone.0022547
PMCID: PMC3150368  PMID: 21829632
7.  Prospective study of Human Papillomavirus and Risk of Cervical Adenocarcinoma 
Human papillomaviruses (HPV) are established as a major cause of cervical carcinoma. However, causality inference is dependent on prospective evidence showing that exposure predicts risk for future disease. Such evidence is available for squamous cell carcinoma, but not for cervical adenocarcinoma. We followed a population-based cohort of 994 120 women who participated in cytological screening in Sweden for a median of 6.7 years. Baseline smears from women who developed adenocarcinoma during follow-up (118 women with in situ disease and 164 with invasive disease) and their individually matched controls (1434 smears) were analyzed for HPV using PCR. Conditional logistic regression was used to estimate odds ratios (OR) of future adenocarcinoma with 95% confidence intervals (CI). Being positive for HPV 16 in the first cytologically normal smear was associated with increased risks for both future adenocarcinoma in situ (OR 11.0, 95 % CI 2.6–46.8) and invasive adenocarcinoma (OR 16.0, 95 % CI 3.8–66.7), compared to being negative for HPV 16. Similarly, an HPV 18 positive smear was associated with increased risks for adenocarcinoma in situ (OR 26.0, 95 % CI 3.5–192) and invasive adenocarcinoma (OR 28.0, 95 % CI 3.8–206), compared to an HPV 18 negative smear. Being positive for HPV 16/18 in two subsequent smears was associated with an infinite risk of both in situ and invasive adenocarcinoma. In conclusion, infections with HPV 16 and 18 are detectable up to at least 14 years before diagnosis of cervical adenocarcinoma. Our data provide prospective evidence that the association of HPV16/18 with cervical adenocarcinoma is strong and causal.
doi:10.1002/ijc.25408
PMCID: PMC2930102  PMID: 20473898
Adenocarcinoma; adenocarcinoma in situ; HPV; cervical cancer; prospective
8.  Radical Prostatectomy Versus Watchful Waiting in Localized Prostate Cancer: the Scandinavian Prostate Cancer Group-4 Randomized Trial 
Background
The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.
Methods
From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.
Results
During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).
Conclusion
Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.
doi:10.1093/jnci/djn255
PMCID: PMC2518167  PMID: 18695132
9.  GENESTAT: an information portal for design and analysis of genetic association studies 
We present the rationale, the background and the structure for version 2.0 of the GENESTAT information portal (www.genestat.org) for statistical genetics. The fast methodological advances, coupled with a range of standalone software, makes it difficult for expert as well as non-expert users to orientate when designing and analysing their genetic studies. The ultimate ambition of GENESTAT is to guide on statistical methodology related to the broad spectrum of research in genetic epidemiology. GENESTAT 2.0 focuses on genetic association studies. Each entry provides a summary of a topic and gives links to key papers, websites and software. The flexibility of the internet is utilised for cross-referencing and for open editing. This paper gives an overview of GENESTAT and gives short introductions to the current main topics in GENESTAT, with additional entries on the website. Methods and software developers are invited to contribute to the portal, which is powered by a Wikipedia-type engine and allows easy additions and editing.
doi:10.1038/ejhg.2008.216
PMCID: PMC2986211  PMID: 19002210
statistical genetics; genetic software; internet
10.  HLA-A Confers an HLA-DRB1 Independent Influence on the Risk of Multiple Sclerosis 
PLoS ONE  2007;2(7):e664.
A recent high-density linkage screen confirmed that the HLA complex contains the strongest genetic factor for the risk of multiple sclerosis (MS). In parallel, a linkage disequilibrium analysis using 650 single nucleotide polymorphisms (SNP) markers of the HLA complex mapped the entire genetic effect to the HLA-DR-DQ subregion, reflected by the well-established risk haplotype HLA-DRB1*15,DQB1*06. Contrary to this, in a cohort of 1,084 MS patients and 1,347 controls, we show that the HLA-A gene confers an HLA-DRB1 independent influence on the risk of MS (P = 8.4×10−10). This supports the opposing view, that genes in the HLA class I region indeed exert an additional influence on the risk of MS, and confirms that the class I allele HLA-A*02 is negatively associated with the risk of MS (OR = 0.63, P = 7×10−12) not explained by linkage disequilibrium with class II. The combination of HLA-A and HLA-DRB1 alleles, as represented by HLA-A*02 and HLA-DRB1*15, was found to influence the risk of MS 23-fold. These findings imply complex autoimmune mechanisms involving both the regulatory and the effector arms of the immune system in the triggering of MS.
doi:10.1371/journal.pone.0000664
PMCID: PMC1919434  PMID: 17653284
11.  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 
Breast Cancer Research  2006;8(6):R67.
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 ≥ 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.
doi:10.1186/bcr1623
PMCID: PMC1797028  PMID: 17132159
12.  Linkage Disequilibrium Mapping of CHEK2: Common Variation and Breast Cancer Risk  
PLoS Medicine  2006;3(6):e168.
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.
Rare mutations in the CHEK2 gene are involved in familial breast cancer. This large study among Swedish women did not find an association between common CHEK2 variants and breast cancer.
doi:10.1371/journal.pmed.0030168
PMCID: PMC1457009  PMID: 16671833
13.  Analysis of binary traits: testing association in the presence of linkage 
BMC Genetics  2005;6(Suppl 1):S92.
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.
doi:10.1186/1471-2156-6-S1-S92
PMCID: PMC1866687  PMID: 16451708

Results 1-13 (13)