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Philip S Rosenberg

Publications and source records attributed to Philip S Rosenberg.

At least 19 recordsLinked to original sources
PubMed2007

Estimating age-specific breast cancer risks: a descriptive tool to identify age interactions.

OBJECTIVE: Clarifying age-specific female breast cancer risks and interactions may provide important etiologic clues. METHOD: Using a population-based case-control study in Poland (2000-2003) of 2,386 incident breast cancer cases and 2,502 control subjects aged 25-74 years, we estimated age-specific breast cancer incidence rates according to risk factors. RESULTS: Breast cancer risks were elevated among women with positive family history (FH), younger age at menarche, older age at first full-term birth, nulliparity, exogenous hormonal usage, and reduced physical activity (PA). Notwithstanding overall risks, we observed statistically significant quantitative (non-crossover) and qualitative (crossover) age interactions for all risk factors except for FH and PA. For example, nulliparity compared to parity reduced breast cancer risk among women ages 25-39 years then rates crossed or reversed, after which nulliparity increased relative risks among women ages 40-74 years. CONCLUSION: Though quantitative age interactions could be expected, qualitative interactions were somewhat counterintuitive. If confirmed in other populations, qualitative interactions for a continuous covariate such as age will be difficult to reconcile in a sequential (multistep or monolithic) 'stochastic' breast cancer model. Alternatively, the reversal of relative risks among younger and older women suggests subgroup heterogeneity with different etiologic mechanisms for early-onset and late-onset breast cancer types.

Adult↗
PubMed2006

Multiple hypothesis testing strategies for genetic case-control association studies.

The genetic case-control association study of unrelated subjects is a leading method to identify single nucleotide polymorphisms (SNPs) and SNP haplotypes that modulate the risk of complex diseases. Association studies often genotype several SNPs in a number of candidate genes; we propose a two-stage approach to address the inherent statistical multiple comparisons problem. In the first stage, each gene's association with disease is summarized by a single p-value that controls a familywise error rate. In the second stage, summary p-values are adjusted for multiplicity using a false discovery rate (FDR) controlling procedure. For the first stage, we consider marginal and joint tests of SNPs and haplotypes within genes, and we construct an omnibus test that combines SNP and haplotype analysis. Simulation studies show that when disease susceptibility is conferred by a SNP, and all common SNPs in a gene are genotyped, marginal analysis of SNPs using the Simes test has similar or higher power than marginal or joint haplotype analysis. Conversely, haplotype analysis can be more powerful when disease susceptibility is conferred by a haplotype. The omnibus test tracks the more powerful of the two approaches, which is generally unknown. Multiple testing balances the desire for statistical power against the implicit costs of false positive results, which up to now appear to be common in the literature.

Case-Control Studies↗
PubMed2006

Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.

Patients with biallelic mutations in BRCA2 are in Fanconi anaemia group D1. We analysed the severity of the mutations in 27 cases, classified according to their association with breast cancer in heterozygotes, and their predicted functional effect. Twenty mutations were frameshifts or truncations, three involved splice sites, five were missense variants of unknown severity and two were benign polymorphisms. Five patients had VACTERL-H association. Leukaemia was reported in 13 patients, and solid tumours in 15; 6 patients had two or more malignancies. The cumulative probability of any malignancy was 97% by age 5.2 years. IVS7+1G-->A and IVS7+2T-->G were associated with AML, and 886delGT and 6174delT with brain tumours. However, patients with other alleles remained at very high risk of these events. Missense mutations formed a distinct cluster in a highly conserved region of the BRCA2 protein. The small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, and early onset and high rates of leukaemia and specific solid tumours, and may comprise an extreme variant of Fanconi anaemia. Several of the alleles were not associated with cancer in presumed carriers, and thus counselling presents more uncertainties than usual.

Adult↗
PubMed2006

Effects of estrogen receptor expression and histopathology on annual hazard rates of death from breast cancer.

BACKGROUND: Breast cancer incidence rates vary according to estrogen receptor expression (ER) and histopathology. We hypothesized that annual mortality rates from breast cancer after initial diagnosis (hazard rates) might also vary by ER and histopathology. METHODS: We accessioned the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER, 1992-2002) program to estimate hazard rates according to ER (positive and negative) and histopathology (duct, tubular, lobular, medullary, inflammatory, papillary, and mucinous types). We used spline functions to model hazard rates free of strongly parametric assumptions for ER negative and positive cases overall and by histopathology. RESULTS: Hazard rates for ER negative and ER positive cases were distinct and non-proportional. At 17 months, ER negative hazard rates peaked at 7.5% per year (95% CI, 7.3-7.8% per year) then declined, whereas ER positive hazard rates lacked a sharp early peak and were comparatively constant at 1.5-2% per year. Falling ER negative and constant ER positive hazard rates crossed at 7 years; after which, prognosis was better for ER negative cases. Among ER positive and negative cases, there were proportional and non-proportional hazards according to histopathologic type, but the two basic ER-associated patterns were maintained. CONCLUSIONS: Hazard rates differed quantitatively and qualitatively according to ER and histopathology. These large-scale population-based results seem consistent with genomic studies, demonstrating two main classes of breast cancers with distinct prognoses according to ER expression.

Adenocarcinoma↗
PubMed2006

The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.

In patients with severe congenital neutropenia (SCN), sepsis mortality is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported. We studied 374 patients with SCN and 29 patients with Shwachman-Diamond syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. In SCN, sepsis mortality was stable at 0.9% per year. The hazard of MDS/AML increased significantly over time, from 2.9% per year after 6 years to 8.0% per year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for sepsis mortality and 21% for MDS/AML. A subgroup of SCN patients (29%) received more than the median dose of G-CSF (> or = 8 microg/kg/d), but achieved less than the median absolute neutrophil count (ANC) response (ANC < 2.188 x 10(9)/L [2188/microL] at 6-18 months). In these less-responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared with 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. Risk of MDS/AML may be similar in SDS and SCN. In less-responsive SCN patients, early hematopoietic stem cell transplantation may be a rational option.

Female↗
PubMed2006

Resampling-based multiple hypothesis testing procedures for genetic case-control association studies.

In case-control studies of unrelated subjects, gene-based hypothesis tests consider whether any tested feature in a candidate gene--single nucleotide polymorphisms (SNPs), haplotypes, or both--are associated with disease. Standard statistical tests are available that control the false-positive rate at the nominal level over all polymorphisms considered. However, more powerful tests can be constructed that use permutation resampling to account for correlations between polymorphisms and test statistics. A key question is whether the gain in power is large enough to justify the computational burden. We compared the computationally simple Simes Global Test to the min P test, which considers the permutation distribution of the minimum p-value from marginal tests of each SNP. In simulation studies incorporating empirical haplotype structures in 15 genes, the min P test controlled the type I error, and was modestly more powerful than the Simes test, by 2.1 percentage points on average. When disease susceptibility was conferred by a haplotype, the min P test sometimes, but not always, under-performed haplotype analysis. A resampling-based omnibus test combining the min P and haplotype frequency test controlled the type I error, and closely tracked the more powerful of the two component tests. This test achieved consistent gains in power (5.7 percentage points on average), compared to a simple Bonferroni test of Simes and haplotype analysis. Using data from the Shanghai Biliary Tract Cancer Study, the advantages of the newly proposed omnibus test were apparent in a population-based study of bile duct cancer and polymorphisms in the prostaglandin-endoperoxide synthase 2 (PTGS2) gene.

Algorithms↗
PubMed2005

Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China.

There is evidence that chronic inflammation predisposes to biliary tract cancer and that use of non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Although the mechanisms by which NSAIDs lower cancer risk remain unclear, NSAIDs reduce prostaglandin production by blocking prostaglandin-endoperoxide synthase 2 (PTGS2, commonly known as COX-2), an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue. Since variants in the PTGS2 gene may modify the expression or function of its encoded enzyme to modulate the inflammatory response in the biliary tract, we examined the associations of eight PTGS2 polymorphisms (-645C-->T; Ex3 -8G-->C; IVS5 -275T-->G; IVS7 +111T-->C; Ex10 +127T-->C; Ex10 +686 --->ATTAT-->TTATA; Ex10 +837T-->C; Ex10 -90C-->T) with biliary tract cancer and stones in a population-based case-control study conducted in Shanghai, China. Genotyping was performed for 411 patients with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater), 895 patients with biliary stones (673 gallbladder, 222 bile duct), and 786 healthy individuals randomly selected from the population. Significant associations were seen only between the Ex10 +837T-->C marker and bile duct cancer risk. Relative to individuals with the TT genotype, those carrying the C allele (TC or CC genotype) had a 1.8-fold (95% confidence interval: 1.2-2.7) risk of bile duct cancer. Inferred haplotypes including this risk-conferring allele were also associated with increased bile duct cancer risk of similar magnitude. Our results suggest that a common PTGS2 variant increases bile duct cancer risk. Further investigation is needed to confirm and extend our findings in studies of biliary tract cancer that more comprehensively examine PTGS2 and other inflammation-related genes.

Age Factors↗
PubMed2005

Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers.

PURPOSE: Breast cancer penetrance estimates in BRCA1 mutation carriers have varied from 40% to 85%; this heterogeneity has been attributed to variations in risk among different study populations. No study has taken oophorectomy status into account in estimating penetrance. Because prophylactic oophorectomy reduces breast cancer risk by approximately 50%, we hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates. METHODS: Females from multiple-case breast/ovarian cancer families that segregate deleterious BRCA1 mutations were observed prospectively for breast cancer incidence and oophorectomy. RESULTS: Within this cohort, 33 cases of breast cancer developed in 98 women with deleterious BRCA1 mutations during follow-up, yielding an estimated cumulative lifetime breast cancer risk of 80%. This estimate increased to 94% when the study participants were censored at the time of oophorectomy. Six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with 27 of 65 mutation carriers with intact ovaries (hazard ratio = 0.38; 95% CI, 0.15 to 0.97). Estimates of absolute breast cancer risk demonstrated that the protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery. When surgical status was ignored, the strong protective effect of oophorectomy, coupled with the high prevalence of the procedure in these families, led to a significantly lower estimate of the breast cancer penetrance in BRCA1 mutation carriers. CONCLUSION: Differing rates of oophorectomy likely represent an underappreciated basis for a portion of the heterogeneity in estimated breast cancer penetrance described in BRCA mutation carriers, particularly mutation carriers from extensively affected, multiple-case families.

Adult↗
PubMed2005

Assessing uncertainty in reference intervals via tolerance intervals: application to a mixed model describing HIV infection.

We define the reference interval as the range between the 2.5th and 97.5th percentiles of a random variable. We use reference intervals to compare characteristics of a marker of disease progression between affected populations. We use a tolerance interval to assess uncertainty in the reference interval. Unlike the tolerance interval, the estimated reference interval does not contains the true reference interval with specified confidence (or credibility). The tolerance interval is easy to understand, communicate and visualize. We derive estimates of the reference interval and its tolerance interval for markers defined by features of a linear mixed model. Examples considered are reference intervals for time trends in HIV viral load, and CD4 per cent, in HIV-infected haemophiliac children and homosexual men. We estimate the intervals with likelihood methods and also develop a Bayesian model in which the parameters are estimated via Markov-chain Monte Carlo. The Bayesian formulation naturally overcomes some important limitations of the likelihood model.

Adult↗
PubMed2005

Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia.

People with hemophilia were formerly at very high risk of infection with hepatitis C virus (HCV). Approximately 20% of HCV-infected patients spontaneously clear the virus. To identify correlates of spontaneous clearance of HCV, we studied a cohort of HCV-infected hemophilic subjects without human immunodeficiency virus infection who had never been treated with interferon. Plasma HCV RNA was persistently undetectable in 192 (27.0%) of 712 HCV-seropositive subjects. In multivariate analyses, HCV clearance was more likely in subjects infected with HCV at younger age, especially with infection before age 2 years (40.1%) compared with after age 15 years (14.9%, P(trend) < .0001), and with relatively recent infection, especially after 1983 (42.8%) compared with before 1969 (18.2%, P(trend) < .0001). HCV clearance was marginally reduced with African ancestry (19%) and greatly increased with chronic hepatitis B virus (HBV) infection (59.1%, P = .001). Resolved HBV infection, coagulopathy types and severity, types of clotting factor treatment, and sex were not associated with HCV clearance. In conclusion, hemophilic subjects coinfected with chronic HBV and those infected with HCV before age 2 years or after 1983 were significantly more likely to spontaneously clear HCV viremia. These data highlight and clarify the importance of nongenetic determinants in spontaneous recovery from HCV infection.

Adolescent↗
PubMed2005

Secular trends in outcomes for Fanconi anemia patients who receive transplants: implications for future studies.

Transplantation protocols for patients with Fanconi anemia are being modified continuously. However, it is unclear how outcomes have changed over time. We determined historical adverse event rates from long-term follow-up of 117 Fanconi anemia patients in the Hôpital Saint Louis transplant cohort, who received low-dose cyclophosphamide- and irradiation-based conditioning, in combination with other modalities, between 1976 and October 2002. In high-risk patients with mismatched donors, the peritransplantation mortality rate during 0 to 6 months declined significantly over time (P = .003), from 28%/month (95% confidence interval [CI], 9%-87%/month) during 1985 to 1989 to 3.3%/month (95% CI, 0.8%-13.3%/month) during 2000 to October 2002. The corresponding proportion of patients who developed severe acute graft-versus-host disease also declined significantly over time (P = .003). In low-risk patients with matched sibling donors, the peritransplantation mortality rate was consistently low, 1.4%/month (95% CI, 0.3%-5.3%/month), during 1990 to October 2002. Sample sizes to detect 2-fold reductions from rates and risks observed since the mid-1990s are larger than recently reported case series. To demonstrate further advances in survival, transplant centers may need to coordinate their protocols and engage in multicenter collaborative studies.

Bone Marrow Transplantation↗
PubMed2004

Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants.

Hematopoietic stem cell transplant (SCT) is currently the only therapy that can restore normal hematopoiesis in patients with Fanconi anemia (FA). Patients with FA have a high baseline risk of squamous cell cancers (SCCs) of the head, neck, and esophagus, and SCT conditioning may increase SCC incidence. We evaluated the risks of SCC and death in 145 patients with FA in the North American Survey (NAS) cohort who did not receive transplants, and 117 patients with FA in the Hôpital Saint Louis (SLH) cohort who did receive transplants. The age-specific hazard of SCC was 4.4-fold higher in patients who received transplants than in those who did not (P = .003), and SCCs occurred at significantly younger ages in the former (respective medians, 18 and 33 years, P = .004). Survival after SCC was similarly poor in both cohorts (P = .135, median, 13 months). The hazard of SCC increased at a greater than linear rate, to 4.4% per year by age 40 in NAS and 4.7% per year by 10 years after transplant in SLH. In SLH, the hazard of non-SCC death was biphasic, declining significantly (P = .004) from 7.1% per month during the first 6 months after transplant to 0.13% per month (1.6% per year) after the first year. Acute and chronic graft-versus-host diseases were significant SCC risk factors. Adverse event rates in these cohorts provide historical control rates to assess emerging therapies for FA.

Adolescent↗
PubMed2004

Individualized risks of first adverse events in patients with Fanconi anemia.

Fanconi anemia (FA) is an autosomal recessive condition associated with bone marrow failure (BMF) leading to death or hematopoietic stem cell transplantation, acute myeloid leukemia (AML), and solid tumors (STs). It is unclear which patients are most likely to develop each outcome. From a cohort of 144 North American patients with FA, we calculated individualized risks of each outcome, given the presence or absence of readily diagnosed congenital abnormalities that occur frequently in FA. Abnormal radii and a 5-item congenital abnormality score were significant risk factors for BMF. The cumulative incidence of BMF by age 10 years varied from 18% in the lowest BMF risk group to 83% in the highest. Because of competing risks, patients in the lowest BMF risk group were most likely to live long enough to develop AML or ST, and, conversely, patients in the highest BMF risk group were least likely to live long enough to develop AML or ST. By age 40, the cumulative incidence of ST ranged from 0.6% to 29% in the highest and lowest BMF risk groups, respectively. Abnormal radii are the strongest predictor of early BMF in FA; a congenital abnormality score separates patients with normal radii into distinct prognostic groups.

Acute Disease↗
PubMed2003

Quantifying epidemiologic risk factors using non-parametric regression: model selection remains the greatest challenge.

Logistic regression is widely used to estimate relative risks (odds ratios) from case-control studies, but when the study exposure is continuous, standard parametric models may not accurately characterize the exposure-response curve. Semi-parametric generalized linear models provide a useful extension. In these models, the exposure of interest is modelled flexibly using a regression spline or a smoothing spline, while other variables are modelled using conventional methods. When coupled with a model-selection procedure based on minimizing a cross-validation score, this approach provides a non-parametric, objective, and reproducible method to characterize the exposure-response curve by one or several models with a favourable bias-variance trade-off. We applied this approach to case-control data to estimate the dose-response relationship between alcohol consumption and risk of oral cancer among African Americans. We did not find a uniquely 'best' model, but results using linear, cubic, and smoothing splines were consistent: there does not appear to be a risk-free threshold for alcohol consumption vis-à-vis the development of oral cancer. This finding was not apparent using a standard step-function model. In our analysis, the cross-validation curve had a global minimum and also a local minimum. In general, the phenomenon of multiple local minima makes it more difficult to interpret the results, and may present a computational roadblock to non-parametric generalized additive models of multiple continuous exposures. Nonetheless, the semi-parametric approach appears to be a practical advance.

Black or African American↗
PubMed2003

Effects of CCR5-delta32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis.

OBJECTIVE: Among perinatally infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of CCR5-delta32 and CCR2-64I in an international meta-analysis. METHODS: Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated. RESULTS: There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-delta32 and CCR2-64I showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (CI) 0.58-1.23; and 0.87, 95% CI 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-delta32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43-2.10) in later years (P=0.01 for the time-dependent model). For CCR2-64I, the hazard ratio for death was 0.69 (95% CI 0.39-1.21) in the first 6 years of life and 2.56 (95% CI 1.26-5.20) in subsequent years (P<0.01 for the time-dependent model). CCR5-delta32 and CCR2-64I offered no clear protection after clinical AIDS had developed. CONCLUSION: The CCR5-delta32 and CCR2-64I alleles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.

Alleles↗
PubMed2003

Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40.

BACKGROUND: Early poliovirus vaccines were accidentally contaminated with simian virus 40 (SV40). In Denmark, poliovirus vaccine was administered to most children from 1955 through 1961. SV40 DNA sequences have been detected in several human malignancies, including mesothelioma, ependymoma, choroid plexus tumors, and non-Hodgkin's lymphoma. To clarify whether SV40 infection increases risk of these cancers or of cancers arising in children, we examined cancer incidence in three Danish birth cohorts. METHODS: Population-based cancer incidence data from 1943 through 1997 were obtained from the Danish Cancer Registry. The relationship between exposure to SV40-contaminated vaccine and cancer incidence was evaluated by examining incidence in birth cohorts that differed in exposure to SV40-contaminated vaccine. In addition, cancer incidence was examined in children who were 0-4 years of age before, during, and after the period of vaccine contamination. Incidence was compared using Poisson regression, adjusting for age differences. All statistical tests were two-sided. RESULTS: After 69.5 million person-years of follow-up, individuals exposed to SV40-contaminated poliovirus vaccine as infants (i.e., born 1955-1961) or children (i.e., born 1946-1952) had lower overall cancer risk (age-adjusted relative risk [RR] = 0.86, 95% confidence interval [CI] = 0.81 to 0.91 and RR = 0.79, 95% CI = 0.75 to 0.84, respectively; P<.001 for both) than unexposed individuals (i.e., born 1964-1970, after the vaccine was cleared of SV40 contamination). Specifically, SV40 exposure was not associated with increased incidence of mesothelioma, ependymoma, choroid plexus tumor, or non-Hodgkin's lymphoma. After 19.5 million person-years of follow-up, incidence of all cancers combined, of intracranial tumors, and of leukemia among children aged 0-4 years was also not associated with SV40 exposure. Ependymoma incidence was higher during the exposed period than during the unexposed period (RR = 2.59, 95%CI = 1.36 to 4.92; P =.004 versus the period before contamination); however, incidence peaked in 1969, after the vaccine was cleared of SV40. CONCLUSION: Exposure to SV40-contaminated poliovirus vaccine in Denmark was not associated with increased cancer incidence.

Child, Preschool↗