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1.  Overdiagnosis in Low-Dose Computed Tomography Screening for Lung Cancer 
JAMA internal medicine  2014;174(2):269-274.
Screening for lung cancer has the potential to reduce mortality, but in addition to detecting aggressive tumors, screening will also detect indolent tumors that otherwise may not cause clinical symptoms. These overdiagnosis cases represent an important potential harm of screening because they incur additional cost, anxiety, and morbidity associated with cancer treatment.
To estimate overdiagnosis in the National Lung Screening Trial (NLST).
We used data from the NLST, a randomized trial comparing screening using low-dose computed tomography (LDCT) vs chest radiography (CXR) among 53 452 persons at high risk for lung cancer observed for 6.4 years, to estimate the excess number of lung cancers in the LDCT arm of the NLST compared with the CXR arm.
We calculated 2 measures of overdiagnosis: the probability that a lung cancer detected by screening with LDCT is an overdiagnosis (PS), defined as the excess lung cancers detected by LDCT divided by all lung cancers detected by screening in the LDCT arm; and the number of cases that were considered overdiagnosis relative to the number of persons needed to screen to prevent 1 death from lung cancer.
During follow-up, 1089 lung cancers were reported in the LDCT arm and 969 in the CXR arm of the NLST. The probability is 18.5% (95% CI, 5.4%–30.6%) that any lung cancer detected by screening with LDCT was an overdiagnosis, 22.5% (95% CI, 9.7%–34.3%) that a non-small cell lung cancer detected by LDCT was an overdiagnosis, and 78.9% (95% CI, 62.2%–93.5%) that a bronchioalveolar lung cancer detected by LDCT was an overdiagnosis. The number of cases of overdiagnosis found among the 320 participants who would need to be screened in the NLST to prevent 1 death from lung cancer was 1.38.
More than 18% of all lung cancers detected by LDCT in the NLST seem to be indolent, and overdiagnosis should be considered when describing the risks of LDCT screening for lung cancer.
PMCID: PMC4040004  PMID: 24322569
2.  National Lung Screening Trial Findings by Age: Medicare-Eligible Versus Under-65 Population 
Annals of internal medicine  2014;161(9):627-633.
The NLST (National Lung Screening Trial) showed reduced lung cancer mortality in high-risk participants (smoking history of ≥30 pack-years) aged 55 to 74 years who were randomly assigned to screening with low-dose computed tomography (LDCT) versus those assigned to chest radiography. An advisory panel recently expressed reservations about Medicare coverage of LDCT screening because of concerns about performance in the Medicare-aged population, which accounted for only 25% of the NLST participants.
To examine the results of the NLST LDCT group by age (Medicare-eligible vs. <65 years).
Secondary analysis of a group from a randomized trial (NCT00047385).
33 U.S. screening centers.
19 612 participants aged 55 to 64 years (under-65 cohort) and 7110 participants aged 65 to 74 years (65+ cohort) at randomization.
3 annual rounds of LDCT screening.
Demographics, smoking and medical history, screening examination adherence and results, diagnostic follow-up procedures and complications, lung cancer diagnoses, treatment, survival, and mortality.
The aggregate false-positive rate was higher in the 65+ cohort than in the under-65 cohort (27.7% vs. 22.0%; P < 0.001). Invasive diagnostic procedures after false-positive screening results were modestly more frequent in the older cohort (3.3% vs. 2.7%; P = 0.039). Complications from invasive procedures were low in both groups (9.8% in the under-65 cohort vs. 8.5% in the 65+ cohort). Prevalence and positive predictive value (PPV) were higher in the 65+ cohort (PPV, 4.9% vs. 3.0%). Resection rates for screen-detected cancer were similar (75.6% in the under-65 cohort vs. 73.2% in the 65+ cohort). Five-year all-cause survival was lower in the 65+ cohort (55.1% vs. 64.1%; P = 0.018).
The oldest screened patient was aged 76 years.
NLST participants aged 65 years or older had a higher rate of false-positive screening results than those younger than 65 years but a higher cancer prevalence and PPV. Screen-detected cancer was treated similarly in the groups.
Primary Funding Source
National Institutes of Health.
PMCID: PMC4505793  PMID: 25199624
3.  Identification of Potential Prognostic Biomarkers in Patients with Untreated, Advanced Pancreatic Cancer from a Phase III Trial (CALGB 80303) 
Cancer  2011;118(2):571-578.
Patients with advanced stage adenocarcinoma of the pancreas have a poor prognosis. The identification of prognostic and/or predictive biomarkers may help stratify patients so that therapy can be individualized.
Serum samples from patients enrolled in the CALGB 80303 Phase III trial, “Randomized Study of Gemcitabine with Versus without Bevacizumab in Patients with Locally Advanced or Metastatic Adenocarcinoma of the Pancreas” were used to discover novel biomarkers. For the discovery phase, 40 sera were selected based on length of survival and type of therapy, and subjected to LC-MS/MS analysis. The top features (proteins) were then further selected for validation by ELISA.
Quantitation by nano-LC-MS/MS resulted in 1452 peptides mapping to 156 proteins across all 40 samples, 92 of which had 2 or more peptides. After curation of the data we selected one putative prognostic protein, alpha-1 antichymotrypsin (AACT), and two putative predictive proteins, histidine-rich glycoprotein (HRG) and complement factor H (CFH) for validation by ELISA. AACT was found to be negatively correlated with overall survival (τ = −0.30 (−0.38, −0.22); p<0.00001). There was no evidence for interaction with bevacizumab and HRG, but there was some evidence for a weak positive correlation of HRG with overall survival (τ = 0.11 (0.03, 0.19); p<0.01). CFH was found to be neither a predictive nor a prognostic factor for overall survival.
AACT may be a useful prognostic marker in patients with advanced stage pancreatic carcinoma, although additional validation studies are needed.
PMCID: PMC3184330  PMID: 21713765
pancreatic neoplasms; prognosis; biological markers; bevacizumab; alpha 1-antichymotrypsin
4.  NLST ACRIN Biomarker Repository Originating from the Contemporary Screening for the Detection of Lung Cancer Trial (NLST, ACRIN 6654):Design, Intent, and Availability of Specimens for Validation of Lung Cancer Biomarkers 
Lung cancer continues to be a major public health problem, and more patients die from this disease than any other cancer. The vast majority of patients present with advanced stage disease when therapeutic options are limited and the overall 5 year survival rate remains approximately 15%. Screening with low dose helical computed tomography (CT)has been suggested for early detection, although the effect on mortality is currently under investigation. As part of the National Lung Cancer Screening Trial, a specimen biorepository including blood, sputum, and urine were collected serially for the primary purpose of validating early detection lung cancer biomarkers. In addition tumor samples have been obtained from patients diagnosed with lung cancer to be included in a tissue microarray. This commentary describes the rationale, composition, intent, and availability of specimen in the biorepository.
PMCID: PMC2963472  PMID: 20871260
5.  Complement Factor H Autoantibodies are Associated with Early Stage NSCLC 
In order to discover diagnostic biomarkers associated with early stage non-small cell lung cancer (NSCLC), we searched for autoantibodies preferentially present in stage I patients compared to patients with advanced stage disease. Here we describe an autoantibody against complement factor H (CFH) and its association with early stage NSCLC.
Experimental Design
Immunoblots were used to detect autoantibodies in the sera of stage I NSCLC patients. An autoantibody recognizing a 150 kDa protein was discovered and the protein was identified by mass spectrometry. The association of the autoantibody with early stage disease was suggested by the results of immunoblot analysis with sera from 28 stage I patients and 28 stage III/IV patients. This association was confirmed by protein microarray of sera from 125 NSCLC patients of all stages as well as 125 age, gender, and smoking history matched controls.
The immunoreactive protein was identified as CFH. By immunoblot analysis, anti-CFH autoantibody was found in 50% of stage I NSCLC patients and 11% of late stage NSCLC patients (P=0.003). By protein microarray analysis, patients with stage I NSCLC had a significantly higher incidence of anti-CFH antibody than those with late stage NSCLC (P=0.0051). The percentage of sera with a positive level of CFH autoantibody was 30.4% in stage I, 21.1% in stage II, 12.5% in stage III, 7.4% in stage IV and 8.0% in the control group.
These findings suggest that in patients with NSCLC, CFH autoantibody is a molecular marker associated with early stage disease.
PMCID: PMC2891404  PMID: 20515868
Lung Cancer; Metastasis; Complement Factor H; Autoimmunity
6.  Preliminary Evaluation of Biplane Correlation (BCI) Stereographic Imaging for Lung Nodule Detection 
Journal of Digital Imaging  2012;26(1):109-114.
A biplane correlation (BCI) imaging system obtains images that can be viewed in stereo, thereby minimizing overlapping structures. This study investigated whether using stereoscopic visualization provides superior lung nodule detection compared to standard postero-anterior (PA) image display. Images were acquired at two oblique views of ±3° as well as at a standard PA position from 60 patients. Images were processed using optimal parameters and displayed on a stereoscopic display. The PA image was viewed in the standard format, while the oblique views were paired to provide a stereoscopic view of the subject. A preliminary observer study was performed with four radiologists who viewed and scored the PA image then viewed and scored the BCI stereoscopic image. The BCI stereoscopic viewing of lung nodules resulted in 71 % sensitivity and 0.31 positive predictive value (PPV) index compared to PA results of 86 % sensitivity and 0.26 PPV index. The sensitivity for lung nodule detection with the BCI stereoscopic system was reduced by 15 %; however, the total number of false positives reported was reduced by 35 % resulting in an improved PPV index of 20 %. The preliminary results indicate observer dependency in terms of relative advantage of either system in the detection of lung nodules, but overall equivalency of the two methods with promising potential for BCI as an adjunct diagnostic technique.
PMCID: PMC3553371  PMID: 22422436
Chest radiographs; 3D imaging (imaging, three dimensional); Digital display; Image acquisition; Imaging; Three dimensional; Radiographic magnification; Radiography; Biplane correlation imaging; Stereomammography; Stereoradiography
7.  Discovery of Novel Cyclophilin A Ligands Using an H/D Exchange- and Mass Spectrometry-Based Strategy 
Journal of biomolecular screening  2010;15(9):1051-1062.
Cyclophilin A (CypA) is an overexpressed protein in lung cancer tumors and as a result is a potential therapeutic and diagnostic target. Here we utilize an H/D exchange- and MALDI mass spectrometry-based assay, termed single-point SUPREX (Stability of Unpurified Proteins from Rates of H/D Exchange), to screen two chemical libraries, including the 1280-compound LOPAC library and the 9600 compound DIVERSet library, for binding to CypA. This work represents the first application of single-point SUPREX using a pooled ligand approach, which we demonstrate is capable of screening rates as fast as six seconds/ligand. The false positive and false negative rates determined in the current work using a set of control samples were 0% and 9%, respectively. A false positive rate of 20% was found in screening the actual libraries. Eight novel ligands to CypA were discovered including: 2-(α-naphthoyl)ethyltrimethyl-ammonium iodide, (E)-3-(4-t-Butylphenylsulfonyl)-2-propenenitrile, 3-(N-benzyl-N-isopropyl)amino-1-(naphthalen-2-yl)propan-1-one, cis-diammineplatinum (II) chloride, 1-(3,5-dichlorophenyl)-1H-pyrrole-2,5-dione, N-(3-chloro-1,4-dioxo-1,4-dihydro-2-naphthalenyl)-N-cyclohexylacetamide, 1-[2-(3,4-dimethoxyphenyl)ethyl]-1H-pyrrole-2,5-dione, and 4-(2-methoxy-4-nitrophenyl)-1-methyl-10-oxa-4-azatricyclo[,6~]dec-8-ene-3,5-dione. These compounds, which had moderate binding affinities to CypA (i.e., Kd values in the low micromolar range), provide new molecular scaffolds that might be useful in the development of CypA targeted diagnostic imaging or therapeutic agents for lung cancer.
PMCID: PMC3197229  PMID: 20855564
Cyclophilin A; Matrix-Assisted Laser Desorption/Ionization; amide H/D exchange; high-throughput screening
8.  An H/D Exchange- and Protease Digestion-Based Screening Assay for Protein-Ligand Binding Detection 
Analytical chemistry  2009;81(16):6860-6867.
A protease digestion strategy was incorporated into single-point SUPREX (stability of unpurified proteins from rates of H/D exchange), which is an H/D exchange- and mass spectrometry-based assay for the detection of protein-ligand binding. Single-point SUPREX is an abbreviated form of SUPREX in which protein-ligand binding interactions are detected by measuring the increase in a protein’s thermodynamic stability upon ligand binding. The new protease digestion protocol provides a noteworthy increase in the efficiency of single-point SUPREX because peptide masses can be determined with greater precision than intact protein masses in the MALDI readout of single-point SUPREX. The protocol was evaluated in test screens on two model protein systems, including cyclophilin A (CypA) and the minor allele variant of human alanine:glyoxylate aminotransferase (AGTmi). The test screening results obtained on both proteins revealed that the peptide readout of the single-point SUPREX-protease digestion protocol was more efficient than the intact protein readout of the original single-point SUPREX protocol at discriminating hits and non-hits. In addition to this improvement in screening efficiency, the protease digestion strategy described here is expected to significantly increase the generality of the single-point SUPREX assay.
PMCID: PMC2858457  PMID: 20337380
9.  Validation of Two Models to Estimate the Probability of Malignancy in Patients with Solitary Pulmonary Nodules 
Thorax  2007;63(4):335-341.
Effective strategies for managing patients with solitary pulmonary nodules (SPN) depend critically on the pre-test probability of malignancy.
To validate two previously developed models that estimate the probability that an indeterminate solitary pulmonary nodule (SPN) is malignant, based on clinical characteristics and radiographic findings.
We retrospectively collected data on age, smoking and cancer history, nodule size, location, and spiculation from the medical records of 151 veterans (145 men, 6 women; range 39 to 87 years) with an SPN measuring 7 to 30 mm (inclusive) and a final diagnosis established by histopathology or 2-year follow-up. We compared each patient's final diagnosis to the probability of malignancy predicted by two models: one developed by investigators at the Mayo Clinic and another that we developed from patients enrolled in a VA Cooperative Study. We assessed model accuracy by calculating areas under the receiver operating characteristic (ROC) curve and model calibration by comparing predicted and observed rates of malignancy.
The area under the ROC curve for the Mayo Clinic model (0.80; 95% CI 0.72-0.88) was higher than that of the VA model (0.73; 95% CI 0.64-0.82), but this difference was not statistically significant (P=0.10). Calibration curves showed that the probability of malignancy was underestimated by the Mayo Clinic model and overestimated by the VA model.
Two existing prediction models are sufficiently accurate to guide decisions about the selection and interpretation of subsequent diagnostic tests in patients with SPNs, although clinicians should also consider the prevalence of malignancy in their practice setting when choosing a model.
PMCID: PMC2882437  PMID: 17965070
Lung Neoplasms; Coin Lesion; pulmonary; Diagnosis; Models; statistical; Receiver Operating Characteristic (ROC) curve
10.  Throughput and Efficiency of a Mass Spectrometry-Based Screening Assay for Protein-Ligand Binding Detection 
An H/D exchange- and MALDI mass spectrometry-based screening assay was applied to search for novel ligands that bind to cyclophilin A, a potential therapeutic and diagnostic target in lung cancer. The assay is based on SUPREX (stability of unpurified proteins from rates of H/D exchange), which exploits the H/D exchange properties of amide protons to measure the increase in a protein's thermodynamic stability upon ligand binding in solution. The current study evaluates the throughput and efficiency with which 880 potential ligands from the Prestwick Chemical Library could be screened for binding to cyclophilin A. Screening was performed at a rate of 3 min/ligand using a conventional MALDI mass spectrometer. False positive and false negative rates, based on a set of control data, were as low as 0% and 9%, respectively. Based on the 880-member library screening, a false positive rate of 0% was observed when a 2-tier selection strategy was implemented. Although novel ligands for cyclophilin A were not discovered, cyclosporin A, a known ligand to CypA and a blind control in the library, was identified as a hit. We also describe a new strategy to eliminate some of the complications related to back exchange that can arise in screening applications of SUPREX.
PMCID: PMC2563801  PMID: 18653356
11.  Characterising phase variations in MALDI-TOF data and correcting them by peak alignment 
Cancer Informatics  2007;1(1):32-40.
The use of MALDI-TOF mass spectrometry as a means of analyzing the proteome has been evaluated extensively in recent years. One of the limitations of this technique that has impeded the development of robust data analysis algorithms is the variability in the location of protein ion signals along the x-axis. We studied technical variations of MALDI-TOF measurements in the context of proteomics profiling. By acquiring a benchmark data set with five replicates, we estimated 76% to 85% of the total variance is due to phase variation. We devised a lobster plot, so named because of the resemblance to a lobster claw, to help detect the phase variation in replicates. We also investigated a peak alignment algorithm to remove the phase variation. This operation is analogous to the normalization step in microarray data analysis. Only after this critical step can features of biological interest be clearly revealed. With the help of principal component analysis, we demonstrated that after peak alignment, the differences among replicates are reduced. We compared this approach to peak alignment with a model-based calibration approach in which there was known information about peaks in common among all spectra. Finally, we examined the potential value at each point in an analysis pipeline of having a set of methods available that includes parametric, semiparametric and nonparametric methods; among such methods are those that benefit from the use of prior information.
PMCID: PMC2657651  PMID: 19305630
variation; amplitude; phase; MALDI-TOF; peak alignment

Results 1-11 (11)