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1.  SELDI-TOF MS Whole Serum Proteomic Profiling with IMAC Surface Does Not Reliably Detect Prostate Cancer 
Clinical chemistry  2007;54(1):53-60.
BACKGROUND
The analysis of bodily fluids using SELDI-TOF MS has been reported to identify signatures of spectral peaks that can be used to differentiate patients with a specific disease from normal or control patients. This report is the 2nd of 2 companion articles describing a validation study of a SELDI-TOF MS approach with IMAC surface sample processing to identify prostatic adenocarcinoma.
METHODS
We sought to derive a decision algorithm for classification of prostate cancer from SELDI-TOF MS spectral data from a new retrospective sample cohort of 400 specimens. This new cohort was selected to minimize possible confounders identified in the previous study described in the companion paper.
RESULTS
The resulting new classifier failed to separate patients with prostate cancer from biopsy-negative controls; nor did it separate patients with prostate cancer with Gleason scores <7 from those with Gleason scores ≥7.
CONCLUSIONS
In this, the 2nd stage of our planned validation process, the SELDI-TOF MS– based protein expression profiling approach did not perform well enough to advance to the 3rd (prospective study) stage. We conclude that the results from our previous studies—in which differentiation between prostate cancer and noncancer was demonstrated—are not generalizable. Earlier study samples likely had biases in sample selection that upon removal, as in the present study, resulted in inability of the technique to discriminate cancer from non-cancer cases.
doi:10.1373/clinchem.2007.091496
PMCID: PMC4332515  PMID: 18024530
2.  Pro–Surfactant Protein B As a Biomarker for Lung Cancer Prediction 
Journal of Clinical Oncology  2013;31(36):4536-4543.
Purpose
Preliminary studies have identified pro–surfactant protein B (pro-SFTPB) to be a promising blood biomarker for non–small-cell lung cancer. We conducted a study to determine the independent predictive potential of pro-SFTPB in identifying individuals who are subsequently diagnosed with lung cancer.
Patients and Methods
Pro-SFTPB levels were measured in 2,485 individuals, who enrolled onto the Pan-Canadian Early Detection of Lung Cancer Study by using plasma sample collected at the baseline visit. Multivariable logistic regression models were used to evaluate the predictive ability of pro-SFTPB in addition to known lung cancer risk factors. Calibration and discrimination were evaluated, the latter by an area under the receiver operating characteristic curve (AUC). External validation was performed with samples collected in the Carotene and Retinol Efficacy Trial (CARET) participants using a case-control study design.
Results
Adjusted for age, sex, body mass index, personal history of cancer, family history of lung cancer, forced expiratory volume in one second percent predicted, average number of cigarettes smoked per day, and smoking duration, pro-SFTPB (log transformed) had an odds ratio of 2.220 (95% CI, 1.727 to 2.853; P < .001). The AUCs of the full model with and without pro-SFTPB were 0.741 (95% CI, 0.696 to 0.783) and 0.669 (95% CI, 0.620 to 0.717; difference in AUC P < .001). In the CARET Study, the use of pro-SFPTB yielded an AUC of 0.683 (95% CI, 0.604 to 0.761).
Conclusion
Pro-SFTPB in plasma is an independent predictor of lung cancer and may be a valuable addition to existing lung cancer risk prediction models.
doi:10.1200/JCO.2013.50.6105
PMCID: PMC3871515  PMID: 24248694
3.  Circulating Levels of 25-hydroxyvitamin D and Prostate Cancer Prognosis 
Cancer epidemiology  2013;37(5):10.1016/j.canep.2013.07.005.
Objectives
Ecological, in vitro, and in vivo studies demonstrate a link between vitamin D and prostate tumor growth and aggressiveness. The goal of this study was to investigate whether plasma concentration of vitamin D is associated with survivorship and disease progression in men diagnosed with prostate cancer.
Methods and Materials
We conducted a population-based cohort study of 1,476 prostate cancer patients to assess disease recurrence/progression and prostate cancer-specific mortality (PCSM) risks associated with serum levels of 25(OH) vitamin D [25(OH)D].
Results
There were 325 recurrence/progression and 95 PCSM events during an average of 10.8 years of follow-up. Serum levels of 25(OH)D were not associated with risk of recurrence/ progression or mortality. Clinically deficient vitamin D levels were associated with an increased risk of death from other causes.
Conclusions
We did not find evidence that serum vitamin D levels measured after diagnosis affect prostate cancer prognosis. Lower levels of vitamin D were associated with risk of non-prostate cancer mortality.
doi:10.1016/j.canep.2013.07.005
PMCID: PMC3864767  PMID: 23972671
Prostatic Neoplasms; Mortality; Prognosis; Vitamin D/blood*; Cohort Studies; Epidemiologic Studies; Humans; Male
4.  Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: Results from a crossover trial 
Scope
By increasing blood folate concentrations, folic acid supplementation reduces risk for neural tube defect-affected pregnancies, and lowers homocysteine concentrations. We assessed response of red blood cell (RBC) and serum folate to folic acid supplementation, and examined association of response with the genetic polymorphism C677T of the methylenetetrahydrofolate NAD(P)H (MTHFR) gene.
Methods and Results
Randomized, controlled, crossover trial with two folic acid supplement treatment periods and a 30-week washout period. The primary outcome is blood folate (serum and RBC) concentrations. Volunteers (n=142) aged 18-69 were randomized to two of three doses (0, 200, and 400 μg) of folic acid for twelve weeks. Serum folate response depended on treatment period with significant responses to 200 μg seen only in the second treatment periods (4.4 ng/mL or 3.4 ng/mL). Additionally, serum folate increased as folic acid dose increased to 400 μg (p< 0.01) and response was greater after the washout period (8.7 ng/mL), than after a 6-week run-in (2.3 ng/mL). The differential change attributable to a daily supplement of 400 μg compared to 200 μg was 96.8 ng/mL; while the change attributable to 400 μg compared to 0 μg was 121.4. Increases in RBC folate concentrations with 400 μg occurred within MTHFR gene mutation (C677T); and in the African American group.
Conclusions
Serum folate concentration is responsive to modest increases in folic acid intake. Red blood cell folate increases only with higher additional doses of folic acid supplementation, and this is true for each MTHFR C677T genotype.
doi:10.1002/mnfr.201200108
PMCID: PMC4132693  PMID: 23456769
Folic acid; fortification; methylenetetrahydrofolate reductase; supplementation
5.  Statin use in relation to prostate cancer outcomes in a population-based patient cohort study 
The Prostate  2013;73(11):1214-1222.
Background
We investigated associations between statin use begun before PCa diagnosis and prostate cancer (PCa) recurrence/progression and PCa-specific mortality (PCSM) in a prospective, population-based cohort study.
Methods
The analysis included 1,001 PCa patients diagnosed in 2002–2005 in King County, Washington. Statin use was assessed at baseline using a detailed in-person interview. Prostate cancer recurrence/progression events and cause-specific survival were ascertained from a follow-up survey and the SEER registry. Multivariable competing risk and Cox proportional hazards regression models were used to assess the risk of PCa outcomes according to categories of statin use.
Results
Of the 1,001 PCa patients in our study, 289 men were ever users of statin drugs. During follow-up, we identified 151 PCa recurrence/progression events and 123 total deaths, including 39 PCa-specific deaths. In unadjusted analysis, the risk of PCa-specific mortality (PCSM) was significantly lower for statin users compared to non-users (1% versus 5% at 10 years; P <0.01). In multivariable analysis, the adjusted hazard ratio of PCSM for statin users versus non-users was 0.19 (95% CI: 0.06, 0.56). Statin use was not associated with overall PCa recurrence/progression and other-cause mortality.
Conclusions
Statin use begun before PCa diagnosis was unrelated to PCa recurrence/progression but was associated with a decrease in risk of PCSM.
doi:10.1002/pros.22671
PMCID: PMC3967507  PMID: 23633265
6.  Association between Body-Mass Index and Risk of Death in More Than 1 Million Asians 
The New England journal of medicine  2011;364(8):719-729.
Background
Most studies that have evaluated the association between the body-mass index (BMI) and the risks of death from any cause and from specific causes have been conducted in populations of European origin.
Methods
We performed pooled analyses to evaluate the association between BMI and the risk of death among more than 1.1 million persons recruited in 19 cohorts in Asia. The analyses included approximately 120,700 deaths that occurred during a mean follow-up period of 9.2 years. Cox regression models were used to adjust for confounding factors.
Results
In the cohorts of East Asians, including Chinese, Japanese, and Koreans, the lowest risk of death was seen among persons with a BMI (the weight in kilograms divided by the square of the height in meters) in the range of 22.6 to 27.5. The risk was elevated among persons with BMI levels either higher or lower than that range — by a factor of up to 1.5 among those with a BMI of more than 35.0 and by a factor of 2.8 among those with a BMI of 15.0 or less. A similar U-shaped association was seen between BMI and the risks of death from cancer, from cardiovascular diseases, and from other causes. In the cohorts comprising Indians and Bangladeshis, the risks of death from any cause and from causes other than cancer or cardiovascular disease were increased among persons with a BMI of 20.0 or less, as compared with those with a BMI of 22.6 to 25.0, whereas there was no excess risk of either death from any cause or cause-specific death associated with a high BMI.
Conclusions
Underweight was associated with a substantially increased risk of death in all Asian populations. The excess risk of death associated with a high BMI, however, was seen among East Asians but not among Indians and Bangladeshis.
doi:10.1056/NEJMoa1010679
PMCID: PMC4008249  PMID: 21345101
7.  Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study 
Purpose
Active surveillance is used to manage low risk prostate cancer. Both PCA3 and TMRPSS2-ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort.
Experimental Design
Post-DRE urine was collected prospectively as part of the multi-institutional Canary Prostate Active Surveillance Study (PASS). PCA3 and TMPRSS2-ERG levels were analyzed in urine collected at study entry. Biomarker scores were correlated to clinical and pathologic variables.
Results
In 387 men, both PCA3 and TMPRSS2-ERG scores were significantly associated with higher volume disease. For a negative repeat biopsy, and 1–10%, 11–33%, ≥34% positive cores, median PCA3 and TMPRSS2-ERG scores increased incrementally (P < 0.005). Both PCA3 and TMPRSS2-ERG scores were also significantly associated with presence of high grade disease. For a negative repeat biopsy, Gleason 6 and Gleason ≥7 cancers, the median PCA3 and TMPRSS2-ERG scores also increased incrementally (P = 0.02 and P = 0.001, respectively). Using the marker scores as a continuous variables, the odds ratio for a biopsy in which cancer was detected versus a negative repeat biopsy (ref) on modeling was 1.41 (95% CI 1.07–1.85), P = 0.01 for PCA3 and 1.28 (95% CI 1.10–1.49), P = 0.001 for TMPRSS2-ERG.
Conclusions
For men on active surveillance both PCA3 and TMPRSS2-ERG appear to stratify risk of having aggressive cancer as defined by tumor volume or Gleason score.
doi:10.1158/1078-0432.CCR-12-3283
PMCID: PMC3674574  PMID: 23515404
prostate cancer; active surveillance; biomarkers
8.  Variation in selenoenzyme genes and prostate cancer risk and survival 
The Prostate  2012;73(7):10.1002/pros.22617.
Background
While several studies showed that selenium may prevent prostate cancer (PCa), few studies have evaluated variation in selenoenzyme genes in relation to PCa risk and survival.
Methods
We studied common variants in seven selenoenzymes genes in relation to risk of PCa and PCa-specific mortality (PCSM). In a population-based case-control study of men of European ancestry (1,309 cases, 1,266 controls), we evaluated 35 common, tagging single nucleotide polymorphisms (SNPs) in GPX1 (n = 2), GPX2 (n = 4), GPX3 (n = 6), GPX4 (n = 6), SEP15 (n = 4), SEPP1 (n = 6), and TXNRD1 (n = 7) in relation to PCa risk, and among cases, associations between these variants and risk of PCSM. We used logistic regression and Cox proportional hazards regression to estimate the relative risk of PCa and PCSM, respectively.
Results
Of the SNPs examined, only GPX1 rs3448 was associated with overall PCa risk with an odds ratio of 0.62 for TT versus CC (95% confidence interval, 0.44–0.88). SNPs in GPX2, GPX3, GPX4, SEP15, and SEPP1 had different risk estimates for PCa in subgroups based on stage and grade. We observed associations between SNPs in GPX4 and TXNRD1 and risk of PCSM. None of these associations, however, remained significant after adjustment for multiple comparisons.
Conclusions
We found evidence that genetic variation in a subset of selenoenzyme genes may alter risk of PCa and PCSM. These results need validation in additional subsets.
doi:10.1002/pros.22617
PMCID: PMC3859305  PMID: 23143801
prostate cancer; risk; mortality; selenoenzyme genes; genetic variation
9.  Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts 
PLoS Medicine  2014;11(4):e1001631.
Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia.
Please see later in the article for the Editors' Summary
Background
Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.
Methods and Findings
We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.
Conclusions
Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries.
Why Was This Study Done?
Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health.
What Did the Researchers Do and Find?
For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women.
What Do These Findings Mean?
These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001631.
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available
The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The UK National Health Services Choices website provides information about the health risks associated with smoking
MedlinePlus has links to further information about the dangers of smoking (in English and Spanish)
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001631
PMCID: PMC3995657  PMID: 24756146
10.  Health Beliefs Associated with Cervical Cancer Screening Among Vietnamese Americans 
Journal of Women's Health  2013;22(3):276-288.
Abstract
Background
Vietnamese American women represent one of the ethnic subgroups at great risk for cervical cancer in the United States. The underutilization of cervical cancer screening and the vulnerability of Vietnamese American women to cervical cancer may be compounded by their health beliefs.
Objective
The objective of this study was to explore the associations between factors of the Health Belief Model (HBM) and cervical cancer screening among Vietnamese American women.
Methods
Vietnamese American women (n=1,450) were enrolled into the randomized controlled trial (RCT) study who were recruited from 30 Vietnamese community-based organizations located in Pennsylvania and New Jersey. Participants completed baseline assessments of demographic and acculturation variables, health care access factors, and constructs of the HBM, as well as health behaviors in either English or Vietnamese.
Results
The rate of those who had ever undergone cervical cancer screening was 53% (769/1450) among the participants. After adjusting for sociodemographic variables, the significant associated factors from HBM included: believing themselves at risk and more likely than average women to get cervical cancer; believing that cervical cancer changes life; believing a Pap test is important for staying healthy, not understanding what is done during a Pap test, being scared to know having cervical cancer; taking a Pap test is embarrassing; not being available by doctors at convenient times; having too much time for a test; believing no need for a Pap test when feeling well; and being confident in getting a test.
Conclusion
Understanding how health beliefs may be associated with cervical cancer screening among underserved Vietnamese American women is essential for identifying the subgroup of women who are most at risk for cervical cancer and would benefit from intervention programs to increase screening rates.
doi:10.1089/jwh.2012.3587
PMCID: PMC3601630  PMID: 23428284
11.  Identification of Osteopontin as a Novel Marker for Early Hepatocellular Carcinoma 
Hepatology (Baltimore, Md.)  2011;55(2):483-490.
This study was to identify a biomarker that could improve α-fetoprotein (AFP) performance in hepatocellular carcinoma (HCC) surveillance among patients with cirrhosis. We performed proteomic profiling of plasma from patients with cirrhosis or HCC and validated selected candidate HCC biomarkers in two geographically distinct cohorts in order to include HCC of different etiologies. Mass spectrometry profiling of highly fractionated plasma from 18 cirrhosis and 17 HCC patients identified osteopontin (OPN) as significantly upregulated in HCC cases compared to cirrhosis controls. OPN levels were subsequently measured in 312 plasma samples collected from 131 HCC patients, 76 cirrhosis patients, 52 chronic hepatitis C (CHC) and B (CHB) patients and 53 healthy controls, in two independent cohorts. OPN plasma levels were significantly elevated in HCC patients compared to cirrhosis, CHC, CHB or healthy controls, in both cohorts. OPN alone or in combination with AFP had significantly better area under the receiver operating characteristic curve compared to AFP in comparing cirrhosis and HCC in both cohorts. OPN overall performance remained higher than AFP in comparing cirrhosis and the following HCC groups: HCV-related HCC, HBV-associated HCC and early HCC. OPN had also a good sensitivity in AFP negative HCC. In a pilot prospective study including 22 patients who developed HCC during follow-up, OPN was already elevated a year prior to diagnosis. Conclusion: OPN was more sensitive than AFP for the diagnosis of HCC in all studied HCC groups. In addition, OPN performance remained intact in samples collected a year prior to diagnosis.
doi:10.1002/hep.24703
PMCID: PMC3914762  PMID: 21953299
biomarker; HCC; early detection; OPN
12.  A model for the design and construction of a resource for the validation of prognostic prostate cancer biomarkers: the Canary Prostate Cancer Tissue Microarray 
Advances in anatomic pathology  2013;20(1):39-44.
Tissue microarrays provide unique resources for rapid evaluation and validation of tissue biomarkers. The Canary Foundation Retrospective Prostate Tissue Microarray Resource used a rigorous statistical design, quota sampling, a variation of the case-cohort study, to select patients for inclusion in a multicenter, retrospective prostate cancer tissue microarray cohort. The study is designed to definitively validate tissue biomarkers of prostate cancer recurrence after radical prostatectomy. Tissue samples from over 1,000 participants treated for prostate cancer with radical prostatectomy between 1995 and 2004 were selected at six participating institutions in the United States and Canada. This design captured the heterogeneity of screening and clinical practices in the contemporary North American population. Standardized clinical data were collected in a centralized database. The project has been informative in several respects. The scale and complexity of assembling tissue microarrays (TMAs) with over 200 cases at each of six sites involved unanticipated levels of effort and time. Our statistical design promises to provide a model for outcome-based studies where tissue localization methods are applied to high-density tissue microarrays.
doi:10.1097/PAP.0b013e31827b665b
PMCID: PMC3535290  PMID: 23232570
Prostate Cancer; Prognosis; Tissue Microarray; quota sampling
13.  Association of Variants in Estrogen-Related Pathway Genes with Prostate Cancer Risk 
The Prostate  2012;73(1):1-10.
Background
Through mediation of estrogen receptors, estradiol has been shown to have both carcinogenic and anti-carcinogenic effects on the prostate. We performed a population-based case-control study to investigate variants in estrogen-related genes ESR1, ESR2, CYP19A1, CYP1A1, and CYP1B1 and the potential association with risk of prostate cancer.
Materials and Methods
We evaluated prostate cancer risk conferred by 73 single nucleotide polymorphisms in 1,304 incident prostate cancer cases and 1,266 age-matched controls. Analysis included stratification by clinical features and assessment of environmental modifiers.
Results
There was evidence of altered risk of developing prostate cancer for variants in ESR1, CYP1A1, and CYP1B1, however, only CYP1B1 rs1056836 retained significance after adjustment for multiple comparisons. An association with risk for more aggressive prostate cancer was observed for variants in ESR1, ESR2, and CYP19A1, but none was significant after adjustment for multiple comparisons. There was no effect modification by obesity.
Conclusions
Germline genetic variation of these estrogen pathway genes may contribute to risk of prostate cancer. Additional studies to validate these results and examine the functional consequence of validated variants are warranted.
doi:10.1002/pros.22534
PMCID: PMC3544476  PMID: 22549291
Estrogen Receptor; Cytochrome P450; Aromatase; Prostate Neoplasm; Polymorphism
14.  EDRN Specimen Reference Sets: Paving the Way for Rapid Evaluation of Potential Biomarkers 
Clinical chemistry  2012;59(1):68-74.
BACKGROUND
The mission of the National Cancer Institute’s Early Detection Research Network (EDRN) is to identify and validate cancer biomarkers for clinical use. Since its inception, EDRN investigators have learned a great deal about the process of validating biomarkers for clinical use. Translational research requires a broad spectrum of research expertise, and coordinating collaborative activities can be challenging. The EDRN has developed a robust triage and validation system that serves the roles of both “facilitator” and “brake”.
CONTENT
The system consists of (i) establishing a reference set of specimens collected under Prospective-specimen-collection-Retrospective-Blinded-Evaluation (PRoBE) design criteria; (ii) using the reference set to pre-validate candidate biomarkers before committing to full scale validation; (iii) doing full scale validation for those markers that succeed in pre-validation; and (iv) ensuring that the reference set is sufficiently large in numbers and volumes of sample that future candidate biomarkers can also be studied with it. This system provides rigorous and efficient evaluation of candidate biomarkers and biomarker panels. Reference sets should also be constructed to enable high quality biomarker discovery research.
SUMMARY
We describe the process of establishing our system and hope it will serve as an example of how to validate biomarkers for clinical application. We also describe the biospecimen reference sets that are available in the EDRN and hope this will encourage the biomarker research community, from academia or industry, to use this resource to advance their biomarkers into clinical use.
doi:10.1373/clinchem.2012.185140
PMCID: PMC3652317  PMID: 23193062
Screening; Diagnosis; Prognosis; Prediction; Validation; Pre-validation
15.  Association of body mass index and risk of death from pancreas cancer in Asians: findings from the Asia Cohort Consortium 
Objective
We aimed to examine the association between BMI and the risk of death from pancreas cancer in a pooled analysis of data from the Asia Cohort Consortium.
Methods
The data for this pooled-analysis included 883,529 men and women from 16 cohort studies in Asian countries. Cox proportional-hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreas cancer mortality in relation to BMI. Seven predefined BMI categories (<18.5, 18.5–19.9, 20.0–22.4, 22.5–24.9, 25.0–27.4, 27.5–29.9, ≥30) were used in the analysis, with BMI of 22.5–24.9 serving as the reference group. The multivariable analyses were adjusted for known risk factors, including age, smoking, and history of diabetes.
Results
We found no statistically significant overall association between each BMI category and risk of death from pancreas cancer in all Asians, and obesity was unrelated to mortality risk in both East Asians and South Asians. Age, smoking, and history of diabetes did not modify the association between BMI and risk of death from pancreas cancer. In planned subgroup analyses among East Asians, an increased risk of death from pancreas cancer among those with a BMI<18.5 was observed for individuals with a history of diabetes; HR = 2.01(95%CI: 1.01–4.00) (p for interaction=0.07).
Conclusion
The data do not support an association between BMI and risk of death from pancreas cancer in these Asian populations.
doi:10.1097/CEJ.0b013e3283592cef
PMCID: PMC3838869  PMID: 23044748
body mass index; insulin resistance; obesity; overweight; pancreatic cancer
16.  Canary Prostate Active Surveillance Study (PASS); Design of a Multi-institutional Active Surveillance Cohort and Biorepository 
Urology  2009;75(2):10.1016/j.urology.2009.05.050.
Active surveillance is a management plan for localized prostate cancer that offers selective delayed intervention upon indication of disease progression, allowing patients to delay or avoid treatment and associated side-effects. Outcomes from centers that promote active surveillance are favorable, with high rates of disease-specific survival. However, there remains a need for prognostic variables or biomarkers that distinguish with high specificity the aggressive cancers that progress on surveillance from the indolent cancers. The Canary Prostate Active Surveillance Study(PASS) is a multicenter study and biorepository that will discover and confirm biomarkers of aggressive disease as defined by histologic, PSA, or clinical criteria.
doi:10.1016/j.urology.2009.05.050
PMCID: PMC3827723  PMID: 19758683
Prostate cancer; Active Surveillance; Clinical Trial
17.  LOGISTIC REGRESSION ANALYSIS WITH STANDARDIZED MARKERS 
The annals of applied statistics  2013;7(3):10.1214/13-AOAS634SUPP.
Two different approaches to analysis of data from diagnostic biomarker studies are commonly employed. Logistic regression is used to fit models for probability of disease given marker values while ROC curves and risk distributions are used to evaluate classification performance. In this paper we present a method that simultaneously accomplishes both tasks. The key step is to standardize markers relative to the non-diseased population before including them in the logistic regression model. Among the advantages of this method are: (i) ensuring that results from regression and performance assessments are consistent with each other; (ii) allowing covariate adjustment and covariate effects on ROC curves to be handled in a familiar way, and (iii) providing a mechanism to incorporate important assumptions about structure in the ROC curve into the fitted risk model. We develop the method in detail for the problem of combining biomarker datasets derived from multiple studies, populations or biomarker measurement platforms, when ROC curves are similar across data sources. The methods are applicable to both cohort and case-control sampling designs. The dataset motivating this application concerns Prostate Cancer Antigen 3 (PCA3) for diagnosis of prostate cancer in patients with or without previous negative biopsy where the ROC curves for PCA3 are found to be the same in the two populations. Estimated constrained maximum likelihood and empirical likelihood estimators are derived. The estimators are compared in simulation studies and the methods are illustrated with the PCA3 dataset.
doi:10.1214/13-AOAS634SUPP
PMCID: PMC3817965  PMID: 24204441
constrained likelihood; empirical likelihood; logistic regression; predictiveness curve; ROC curve
18.  Longitudinal multistage model for lung cancer incidence, mortality, and CT detected indolent and aggressive cancers 
Mathematical biosciences  2012;240(1):20-34.
It is currently not known whether most lung cancers detected by computerized tomography (CT) screening are aggressive and likely to be fatal if left untreated, or if a sizable fraction are indolent and unlikely to cause death during the natural lifetime of the individual. We developed a longitudinal biologically-based model of the relationship between individual smoking histories and the probability for lung cancer incidence, CT screen detection, lung cancer mortality, and other-cause mortality. The longitudinal model relates these different outcomes to an underlying lung cancer disease pathway and an effective other-cause mortality pathway, which are both influenced by the individual smoking history. The longitudinal analysis provides additional information over that available if these outcomes were analyzed separately, including testing if the number of CT detected and histologically-confirmed lung cancers is consistent with the expected number of lung cancers “in the pipeline”. We assume indolent nodules undergo Gompertz growth and are detectable by CT, but do not grow large enough to contribute significantly to symptom-based lung cancer incidence or mortality. Likelihood-based model calibration was done jointly to data from 6,878 heavy smokers without asbestos exposure in the control (placebo) arm of the Carotene and Retinol Efficacy Trial (CARET); and to 3,642 heavy smokers with comparable smoking histories in the Pittsburgh Lung Screening Study (PLuSS), a single-arm prospective trial of low-dose spiral CT screening for diagnosis of lung cancer. Model calibration was checked using data from two other single-arm prospective CT screening trials, the New York University Lung Cancer Biomarker Center (NYU) (n=1,021), and Moffitt Cancer Center (Moffitt) cohorts (n=677). In the PLuSS cohort, we estimate that at the end of year 2, after the baseline and first annual CT exam, that 33.0 (26.9, 36.9)% of diagnosed lung cancers among females and 7.0 (4.9, 11.7)% among males were overdiagnosed due to being indolent cancers. At the end of the PLuSS study, with maximum follow-up of 5.8 years, we estimate that due to early detection by CT and limited follow-up, an additional 2.2 (2.0, 2.4) % of all diagnosed cancers among females and 7.1 (6.7, 8.0) % among males would not have been diagnosed in the absence of CT screening. We also find a higher apparent cure rate for lung cancer among CARET females than males, consistent with the larger indolent fraction of CT detected and histologically confirmed lung cancers among PLuSS females. This suggests that there are significant gender differences in the aggressiveness of lung cancer. Females may have an inherently higher proportion of indolent lung cancers than males, or aggressive lung cancers may be brought into check by the immune system more frequently among females than males.
doi:10.1016/j.mbs.2012.05.008
PMCID: PMC3412888  PMID: 22705252
CT screening; multistage; longitudinal model; lung cancer
19.  Evaluation of known oncoantibodies, HER2, p53, and cyclin B1, in pre-diagnostic breast cancer sera 
Serum autoantibodies, directed against oncogenic proteins, have been frequently detected in the sera of breast cancer patients. It is unknown whether serum antibodies that are identified in patients with established disease could also be detected in patients with newly diagnosed disease or even predate the diagnosis of breast cancer. Using sera collected at the time of treatment, at the time of diagnosis, or prior to the time of diagnosis, the current study aimed to address the temporal relationship between breast cancer development and serum antibody response. Starting from serum antibodies to eight known breast cancer antigens, we first identified four serum antibodies, HER-2/neu, p53, CEA, and cyclin B1, which are significantly increased in the sera collected from breast cancer patients at the time of treatment. These antibodies were also elevated in breast cancer sera collected at the time of diagnosis. Lastly, comparison of antibody responses in pre-diagnostic samples from women prior to the development of breast cancer and in controls demonstrated that antibodies to the HER-2/neu and p53 can be detected in sera that were collected on average more than 150 days before a breast cancer diagnosis. These results demonstrated that serum autoantibodies commonly reported in sera from patients with established disease can also be detected in pre-diagnostic sera and may be useful for the early detection of breast cancer.
doi:10.1158/1940-6207.CAPR-11-0558
PMCID: PMC3790582  PMID: 22715141
serum antibody; breast cancer; early detection
20.  Asymptotic Properties of the Sequential Empirical ROC, PPV and NPV Curves Under Case-Control Sampling 
Annals of statistics  2011;39(6):3234-3261.
The receiver operating characteristic (ROC) curve, the positive predictive value (PPV) curve and the negative predictive value (NPV) curve are three measures of performance for a continuous diagnostic biomarker. The ROC, PPV and NPV curves are often estimated empirically to avoid assumptions about the distributional form of the biomarkers. Recently, there has been a push to incorporate group sequential methods into the design of diagnostic biomarker studies. A thorough understanding of the asymptotic properties of the sequential empirical ROC, PPV and NPV curves will provide more flexibility when designing group sequential diagnostic biomarker studies. In this paper we derive asymptotic theory for the sequential empirical ROC, PPV and NPV curves under case-control sampling using sequential empirical process theory. We show that the sequential empirical ROC, PPV and NPV curves converge to the sum of independent Kiefer processes and show how these results can be used to derive asymptotic results for summaries of the sequential empirical ROC, PPV and NPV curves.
doi:10.1214/11-AOS937
PMCID: PMC3771874  PMID: 24039313
Group Sequential Methods; Empirical Process Theory; Diagnostic Testing
21.  Biases Introduced by Choosing Controls to Match Risk Factors of Cases in Biomarker Research 
Clinical chemistry  2012;58(8):1242-1251.
Background
Selecting controls that match cases on risk factors for the outcome is a pervasive practice in biomarker research studies. Yet, such matching biases estimates of biomarker prediction performance. The magnitudes of bias are unknown.
Methods
We examined the prediction performance of biomarkers and improvements in prediction gained by adding biomarkers to risk factor information. Data simulated from bivariate normal statistical models and data from a study to identify critically ill patients were used. We compared true performance with that estimated from case-control studies that do or do not use matching. Receiver operating characteristic curves quantified performance. We propose a new statistical method to estimate prediction performance from matched studies when data on the matching factors are available for subjects in the population.
Results
Performance estimated with standard analyses can be grossly biased by matching especially when biomarkers are highly correlated with matching risk factors. In our studies, the performance of the biomarker alone was underestimated while the improvement in performance gained by adding the marker to risk factors was overestimated by 2 to 10 fold. We found examples where the relative ranking of two biomarkers for prediction was inappropriately reversed by use of a matched design. The new approach to estimation corrected for bias in matched studies.
Conclusions
To properly gauge prediction performance in the population or the improvement gained by adding a biomarker to known risk factors, matched case-control studies must be supplemented with risk factor information from the population and must be analyzed with nonstandard statistical methods.
doi:10.1373/clinchem.2012.186007
PMCID: PMC3464972  PMID: 22730452
design; diagnosis; prediction; prognosis; receiver operating characteristic curve
22.  Updating Risk Prediction Tools: A Case Study in Prostate Cancer 
Online risk prediction tools for common cancers are now easily accessible and widely used by patients and doctors for informed decision-making concerning screening and diagnosis. A practical problem is as cancer research moves forward and new biomarkers and risk factors are discovered, there is a need to update the risk algorithms to include them. Typically the new markers and risk factors cannot be retrospectively measured on the same study participants used to develop the original prediction tool, necessitating the merging of a separate study of different participants, which may be much smaller in sample size and of a different design. Validation of the updated tool on a third independent data set is warranted before the updated tool can go online. This article reports on the application of Bayes rule for updating risk prediction tools to include a set of biomarkers measured in an external study to the original study used to develop the risk prediction tool. The procedure is illustrated in the context of updating the online Prostate Cancer Prevention Trial Risk Calculator to incorporate the new markers %freePSA and [−2]proPSA measured on an external case control study performed in Texas, U.S.. Recent state-of-the art methods in validation of risk prediction tools and evaluation of the improvement of updated to original tools are implemented using an external validation set provided by the U.S. Early Detection Research Network.
doi:10.1002/bimj.201100062
PMCID: PMC3715690  PMID: 22095849
Calibration; Discrimination; Net Benefit, Risk Prediction; Validation; Prostate Cancer Prevention Trial
23.  Glycosylation Variants of Mucins and CEACAMs as Candidate Biomarkers for the Diagnosis of Pancreatic Cystic Neoplasms 
Annals of surgery  2010;251(5):937-945.
BACKGROUND AND AIMS
Cystic lesions of the pancreas are increasingly being recognized due to the widespread use of high resolution abdominal imaging. Since certain cyst types are precursors to invasive cancer, this situation presents an opportunity to intervene prior to malignant progression. Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions with no malignant potential from those with malignant potential. Here we explored whether glycosylation variants on specific proteins in cyst fluid samples could serve as biomarkers to aid in this diagnosis.
METHODS
We utilized a novel antibody-lectin sandwich microarray method to measure the protein expression and glycosylation of MUC1, MUC5AC, MUC16, CEA, and other proteins implicated in pancreatic neoplasia in cyst fluid samples. Fifty-three cyst fluid samples were obtained from patients with mucinous cystic neoplasms (MCN, n = 17), intraductal papillary mucinous neoplasms (IPMN, n = 15), serous cystadenomas (SC, n = 12), or pseudocysts (PC, n = 9), with confirmation of histologic diagnosis at surgical resection.
RESULTS
The detection of a glycan variant on MUC5AC using the lectin wheat-germ agglutinin discriminated mucin-producing cystic tumors (MCNs + IPMNs) from benign cystic lesions (SC + PC) with a 78% sensitivity at 80% specificity, and when used in combination with cyst fluid CA 19-9 gave a sensitivity of 87% at 86% specificity. These biomarkers performed better than cyst fluid CEA (37%/80% sensitivity/specificity).
CONCLUSIONS
These results demonstrate the value of glycan variants for biomarker discovery and suggest that these biomarkers could greatly enhance the accuracy of differentiating pancreatic cystic tumors. Validation studies will be required to determine the clinical value of these markers.
doi:10.1097/SLA.0b013e3181d7738d
PMCID: PMC3713623  PMID: 20395854
24.  The Impact of Prostate Volume, Number of Biopsy Cores and American Urological Association Symptom Score on the Sensitivity of Cancer Detection Using the Prostate Cancer Prevention Trial Risk Calculator 
The Journal of urology  2013;190(1):70-76.
Purpose
We assessed the independent predictive value of prostate volume, number of biopsy cores and AUASS (American Urological Association symptom score) compared to risk factors included in the PCPTRC (Prostate Cancer Prevention Trial risk calculator for prostate cancer) and PCPTHG (Prostate Cancer Prevention Trial risk calculator for high grade cancer [Gleason grade 7 or greater]).
Materials and Methods
Of 5,519 PCPT (Prostate Cancer Prevention Trial) participants the 4,958 used to construct the PCPTRC with AUASS and prostate specific antigen 10 ng/ml or less were included on logistic regression analysis. Risk algorithms were evaluated in 571 EDRN (Early Detection Research Network) participants using the ROC AUC.
Results
A total of 1,094 participants (22.1%) had prostate cancer, of whom 232 (21.2%) had high grade disease. For prostate cancer prediction higher prostate specific antigen, abnormal digital rectal examination, family history of prostate cancer and number of cores were associated with increased risk, while volume was associated with decreased risk. Excluding prostate volume and number of cores, a history of negative biopsy and increased AUASS were also associated with lower risk. For high grade cancer higher prostate specific antigen, abnormal digital rectal examination, black race and number of cores were associated with increased risk and volume, while AUASS was associated with decreased risk. The AUC of the PCPTRC adjusted for volume and number of cores was 72.7% using EDRN data and 68.2% when adjusted for AUASS alone vs 67.6% for the PCPTRC. For high grade disease the AUC was 74.8% and 74.0%, respectively, vs 73.5% for the PCPTHG.
Conclusions
Adjusted PCPT risk calculators for volume, number of cores and AUASS improve cancer detection.
doi:10.1016/j.juro.2012.12.108
PMCID: PMC3708069  PMID: 23313212
prostate; prostatic neoplasms; risk; algorithms; early detection of cancer
25.  Evaluating Prognostic Accuracy of Biomarkers under Competing Risk 
Biometrics  2011;68(2):388-396.
Summary
To develop more targeted intervention strategies, an important research goal is to identify markers predictive of clinical events. A crucial step towards this goal is to characterize the clinical performance of a marker for predicting different types of events. In this manuscript, we present statistical methods for evaluating the performance of a prognostic marker in predicting multiple competing events. To capture the potential time-varying predictive performance of the marker and incorporate competing risks, we define time- and cause-specific accuracy summaries by stratifying cases based on causes of failure. Such definition would allow one to evaluate the predictive accuracy of a marker for each type of event and compare its predictiveness across event types. Extending the nonparametric crude cause-specific ROC curve estimators by Saha and Heagerty (2010), we develop inference procedures for a range of cause-specific accuracy summaries. To estimate the accuracy measures and assess how covariates may affect the accuracy of a marker under the competing risk setting, we consider two forms of semiparametric models through the cause-specific hazard framework. These approaches enable a flexible modeling of the relationships between the marker and failure times for each cause, while efficiently accommodating additional covariates. We investigate the asymptotic property of the proposed accuracy estimators and demonstrate the finite sample performance of these estimators through simulation studies. The proposed procedures are illustrated with data from a prostate cancer prognostic study.
doi:10.1111/j.1541-0420.2011.01671.x
PMCID: PMC3694786  PMID: 22150576
Biomarker evaluation; Cause-specific Hazard; Competing risk; Negative predictive value; Positive predictive value; Receiver Operating Characteristics Curve (ROC curve); Survival analysis

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