Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×10−9). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
This work describes a new methodology for analyzing genome-wide case-control association studies of diseases with strong correlations to clinical covariates, such as age in prostate cancer and body mass index in type 2 diabetes. Currently, researchers either ignore these clinical covariates or apply approaches that ignore the disease's prevalence and the study's ascertainment strategy. We take an alternative approach, leveraging external prevalence information from the epidemiological literature and constructing a statistic based on the classic liability threshold model of disease. Our approach not only improves the power of studies that ascertain individuals randomly or based on the disease phenotype, but also improves the power of studies that ascertain individuals based on both the disease phenotype and clinical covariates. We apply our statistic to seven datasets over six different diseases and a variety of clinical covariates. We found that there was a substantial improvement in test statistics relative to current approaches at known associated variants. This suggests that novel loci may be identified by applying our method to existing and future association studies of these diseases.
To determine the prevalence of anatomic impediments to interlaminar lumbar epidural steroid injection (LESI) in a community-based population.
Cross-sectional observational study.
Older adults (N=333) sampled irrespective of back pain status.
Main Outcome Measures
Computed tomography evaluation of 5 potential anatomic impediments to interlaminar LESI at the L2-S1 spinal levels, including (1) ligamentum flavum (LF) calcification, (2) interspinous ligament (ISL) calcification, (3) spinous process (SP) contact, (4) the absence of epidural fat in the posterior epidural space, and (5) the presence of fat density superficial to the LF in the midsagittal plane. Independent variables included age, sex, body mass index (BMI), and current smoking.
LF and ISL calcifications were prevalent in 3% to 7% and 2% to 3% of spinal levels, respectively, without significant differences by spinal level. SP contact was most common at the L4-5 level (22%). Absence of posterior epidural fat was very common at L5-S1 (65%), but infrequent at other levels. The presence of midline fat density superficial to LF was most common at L5-S1 (55%). The prevalence of LF calcification, ISL calcification, and SP contact increased with age, but the prevalence of absence of posterior epidural fat and the presence of a midline fat density superficial to LF did not. Sex and smoking status were not associated with the prevalence of anatomic impediments, but higher BMI was associated with a lower prevalence of absence of posterior epidural fat.
Anatomic impediments to interlaminar LESI were common in this community-based population, particularly at the L5-S1 spinal level. Because of the high overall prevalence of anatomic impediments, and differences in prevalence by spinal level, knowledge of the distribution and frequency of these impediments may aid in aspects of decision-making for the interventional spine physician.
Injections; epidural; Low back pain; Pathological conditions; anatomical; Rehabilitation; Spine
Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow-up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for genome-wide association studies (GWAS) of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using 10 independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured 10 SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p-value range: 0.02 to 1.8 × 10−8). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p<0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p-value 0.03; combined p-value 7.3 × 10−5). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p-value 0.03; combined p-value 1.9 × 10−4). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.
Walking limitations caused by neurogenic claudication (NC) are typically assessed with self-reported measures, though objective evaluation of walking utilizing motorized treadmill test (MTT) or self-paced walking tests (SPWT) have periodically appeared in the lumbar spinal stenosis (LSS) literature.
This study compared the validity and responsiveness of MTT and SPWT for assessing walking ability before and after common treatments for NC.
Prospective, observational cohort study
50 adults were recruited from an urban spine center if they had LSS, substantial walking limitations from NC, and were scheduled to undergo surgery (20%) or conservative treatment (80%).
Walking times, distances and speeds along with characteristics of NC symptoms were recorded for MTT and SPWT. Self-reported measures included back and leg pain intensity assessed with 0 – 10 numeric pain scales, disability assessed with Oswestry Disability Index (ODI), walking ability assessed with estimated walking times and distances, and subscales from the Spinal Stenosis Questionnaires (SSQ).
MTT used a level track, and SPWT was conducted in a rectangular hallway. Walking speeds were self-selected and test endpoints were: a) NC, b) fatigue, or c) completed the 30-minute test protocol. Results from MTT and SPWT were compared with each other and with self-reported measures. Internal responsiveness was assessed by comparing changes in initial to post-treatment results, and external responsiveness by comparing walking test results between those that improved with those that did not improve by self-report criteria.
Mean age was 68 years. 58% were male. NC included leg pain (88%), and buttock(s) pain (12%). 5 participants could not safely perform MTT. Walking speeds were faster and distances were greater with SPWT, although results from both tests correlated with each other and with self-reported measures. 72% of participants reported improvement following treatment which was confirmed by significant mean differences in self-reported measures. MTT results did not demonstrate internal responsiveness to change in clinical status following treatment, but SPWT did, with increased mean walking times (6 min) and distances (387 m). When responsiveness was assessed against external criterion, both SPWT and MTT demonstrated substantial divergence with self-reported changes in clinical status and alternative outcome measures.
Both MTT and SPWT can quantify walking abilities in NC. As outcome tools, SPWT demonstrated better internal responsiveness than MTT, but neither test demonstrated adequate external responsiveness. Neither test should be considered as a meaningful substitution for disease specific measures of function.
Common polymorphisms in the N-acetyltransferase 2 gene (NAT2) modify the association between cigarette smoking and bladder cancer and have been hypothesized to determine whether active cigarette smoking increases breast cancer risk. The authors sought to replicate the latter hypothesis in a prospective analysis of 6,900 breast cancer cases and 9,903 matched controls drawn from 6 cohorts (1989–2006) in the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium. Standardized methods were used to genotype the 3 most common polymorphisms that define NAT2 acetylation phenotype (rs1799930, rs1799931, and rs1801280). In unconditional logistic regression analyses, breast cancer risk was higher in women with more than 20 pack-years of active cigarette smoking than in never smokers (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17, 1.39), after controlling for established risk factors other than alcohol consumption and physical inactivity. However, associations were similar for the slow (OR = 1.25, 95% CI: 1.11, 1.39) and rapid/intermediate (OR = 1.24, 95% CI: 1.08, 1.42) acetylation phenotypes, with no evidence of interaction (P = 0.87). These results provide some support for the hypothesis that long-term cigarette smoking may be causally associated with breast cancer risk but underscore the need for caution when interpreting sparse data on gene-environment interactions.
arylamine N-acetyltransferase; breast neoplasms; NAT2 protein, human; polymorphism, single nucleotide; smoking
We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 single nucleotide polymorphisms (SNPs) in 1,145 cases of invasive breast cancer among postmenopausal white women, and 1,142 controls. We identified a set of four SNPs in intron 2 of FGFR2, a tyrosine kinase receptor previously shown to be amplified and/or over-expressed in some breast cancers, as highly associated with breast cancer and we confirmed this association in 1,776 cases and 2,072 controls from three additional studies. In both association testing and ancestral recombination graph analysis, FGFR2 haplotypes were associated with risk of breast cancer. Across the four studies the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP, rs1219648 = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other chromosomal loci most strongly associated with breast cancer in the initial GWAS were not associated with risk in the three replication studies. Our summary results from the GWAS are freely available online in a form that should speed the identification of additional loci conferring risk.
Increased levels of serum immunoglobulin E (IgE) because of allergies have been inversely associated with risk of glioma in observational studies. Despite consistency across studies examining history of allergies and glioma, questions remain as to whether those are causal associations. An inverse association between serum IgE and risk of glioma was reported in a large case–control study, but reverse causality and treatment effects remain potential explanations for those findings.
We combined data from four prospective cohort studies and used a nested case–control design to examine the association between allergy and glioma. We included glioma case subjects who were confirmed from medical or pathology records or from death certificates, and with prediagnostic blood available. We matched three control subjects per case subject, and the final numbers for analyses were 169 case subjects and 520 control subjects. Total IgE, food allergen–specific IgE, and respiratory allergen–specific IgE levels were measured using a highly sensitive fluorescent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression analysis. Stratified analyses were conducted by age and birth cohorts.
Borderline elevated total IgE levels (25–100 kU/L) showed a statistically significant inverse association with glioma (OR = 0.63, 95% CI = 0.42 to 0.93), but no association was noted between elevated IgE (>100 kU/L) and glioma (OR = 0.98, 95% CI = 0.61 to 1.56) compared with clinically normal IgE levels (<25 kU/L). The association between glioma and total IgE was consistent for both men and women. Non-statistically significant inverse associations were noted for elevated IgE levels among individuals born before year 1930 (OR = 0.67, 95% CI = 0.34 to 1.34) and when restricting analyses to highly fatal (deceased within 2 years of diagnosis) glioma case subjects (OR = 0.64, 95% CI = 0.34 to 1.19) compared with individuals with clinically normal IgE levels. No associations were observed for either food allergen–specific or respiratory allergen–specific IgE levels.
Overall, our prospective findings are consistent with recent retrospective studies and support an association between total IgE levels and glioma. However, this association requires further elucidation.
Epidemiological studies have linked shortened telomeres with the development of many cancers. However, recent studies have suggested that longer telomeres may lead to prolonged senescence in melanocytes, providing increased opportunity for malignant transformation. We therefore examined whether shorter pre-diagnostically measured relative telomere length in peripheral blood leukocytes (PBLs) was associated with a decreased risk of cutaneous melanoma. Telomere length in prospectively collected PBLs was measured in incident melanoma cases and age-matched controls selected from participants in three large prospective cohorts: the Women’s Health Initiative Observational Study (WHI-OS), the Health Professionals Follow-up Study (HPFS), and the Nurses’ Health Study (NHS). Shorter telomere lengths were associated with decreased risk of melanoma in each cohort. The p for trend across quartiles was 0.03 in the WHI-OS and 0.008 in the HPFS. When combining these two datasets with published data in the NHS (p for trend, 0.09), compared with individuals in the fourth quartile (the longest telomere lengths), those in the first quartile had an odds ratio of 0.43 (95% CI, 0.28–0.68) (p for trend, 0.0003). Unlike findings for other tumors, shorter telomeres were significantly associated with a decreased risk of melanoma in this study, suggesting a unique role of telomeres in melanoma development.
Telomere length; peripheral blood leukocytes; melanoma; skin cancer; prospective study
We conducted a genome-wide association study on cutaneous basal cell carcinoma (BCC) among 2045 cases and 6013 controls of European ancestry, with follow-up replication in 1426 cases and 4845 controls. A non-synonymous SNP in the MC1R gene (rs1805007 encoding Arg151Cys substitution), a previously well-documented pigmentation gene, showed the strongest association with BCC risk in the discovery set (rs1805007[T]: OR (95% CI) for combined discovery set and replication set [1.55 (1.45–1.66); P= 4.3 × 10−17]. We identified that an SNP rs12210050 at 6p25 near the EXOC2 gene was associated with an increased risk of BCC [rs12210050[T]: combined OR (95% CI), 1.24 (1.17–1.31); P= 9.9 × 10−10]. In the locus on 13q32 near the UBAC2 gene encoding ubiquitin-associated domain-containing protein 2, we also identified a variant conferring susceptibility to BCC [rs7335046 [G]; combined OR (95% CI), 1.26 (1.18–1.34); P= 2.9 × 10−8]. We further evaluated the associations of these two novel SNPs (rs12210050 and rs7335046) with squamous cell carcinoma (SCC) risk as well as melanoma risk. We found that both variants, rs12210050[T] [OR (95% CI), 1.35 (1.16–1.57); P= 7.6 × 10−5] and rs7335046 [G] [OR (95% CI), 1.21 (1.02–1.44); P= 0.03], were associated with an increased risk of SCC. These two variants were not associated with melanoma risk. We conclude that 6p25 and 13q32 are novel loci conferring susceptibility to non-melanoma skin cancer.
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we conducted a multi-stage genome-wide association study and previously reported the results of the first two stages, which identified 16 novel susceptibility loci for PrCa. Here we report the results of stage 3 in which we evaluated 1,536 SNPs in 4,574 cases and 4,164 controls. Ten novel association signals were followed up through genotyping in 51,311 samples in 30 studies through the international PRACTICAL consortium. In addition to previously reported loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2p, 3q, 5p, 6p, 12q and Xq (P=4.0 ×10−8 to P=2.7 ×10−24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified.
To assess the cross-sectional relation of planus foot morphology to ipsilateral knee pain and compartment-specific knee cartilage damage in older adults.
In the Framingham Studies, we adapted the Staheli Arch Index (SAI) to quantify standing foot morphology from pedobarographic recordings. We inquired about knee pain and read 1.5 Tesla MRIs using whole-organ magnetic resonance imaging scoring. Logistic regression compared the odds of knee pain among the most planus feet to the odds among all other feet, and estimated odds within categories of increasing SAI. Similar methods estimated the odds of cartilage damage in each knee compartment. Generalized estimating equations adjusted for age, sex, BMI, and non-independent observations.
Among 1903 participants (mean age 65± 9 years; 56% female), 22% of knees were painful most days. Cartilage damage was identified in 45% of medial TF, 27% of lateral TF, 58% of medial PF, and 42% of lateral PF compartments. Compared with other feet, the most planus feet had 1.3 (95% CI: 1.1, 1.6) times the odds of knee pain (p=0.009), and 1.4 (95% CI: 1.1, 1.8) times the odds of medial TF cartilage damage (p=0.002). Odds of pain (ptrend=0.05) and medial TF cartilage damage (ptrend=0.001) increased linearly across categories of increasing SAI. There was no association between foot morphology and cartilage damage in other knee compartments.
Planus foot morphology is associated with frequent knee pain and medial TF cartilage damage in older adults.
The number of effective knee osteoarthritis (OA) interventions, especially those tailored to specific compartmental involvement, is small. The objective of this study was to determine the efficacy of a realigning patellofemoral (PF) brace in improving pain and function among persons with symptomatic lateral patellofemoral OA.
We conducted a double blind, randomized crossover trial of a realigning PF brace for persons with lateral PF OA. Participants had lateral PF OA with anterior knee symptoms on most days of the month, lateral PF joint space narrowing, and radiographic evidence of a definite osteophyte in the PF joint. We compared two treatments: A) Control treatment consisting of a BioSkin Q Brace with patellar realigning strap removed; and B) Active treatment consisting of a realigning BioSkin Q Brace with the strap applied. For each participant, the trial lasted 18 weeks, including 6 weeks each of active and control treatment period separated by a 6-week washout period. The order of treatments was randomized. The primary outcome was change in knee pain on the visual analog scale (VAS). Secondary outcomes included WOMAC pain, function, and stiffness. An unstructured correlation matrix for observations within participants was used in generalized estimating equation fitting to derive a linear regression model that expressed the relation between the intervention and change in VAS pain.
80 participants (63 F) with a mean age and body mass index of 61 years and 28 kg/m2, respectively, were randomized by order of treatment. A model examining the main effects for change in VAS knee pain (0–100) demonstrated no significant treatment effect (−0.68 VAS units, 95% CI: −6.2, 4.8 units, p=0.81) and no differential carryover effect. There was also no significant difference between active and control treatments for WOMAC pain, function, or stiffness outcomes.
The effects of a specific realigning patellofemoral brace are not of clinical or statistical significance.
Patellofemoral osteoarthritis; brace
Patellar bracing is a mechanical treatment strategy for patellofemoral osteoarthritis (OA) that aims to unload the lateral compartment of the joint by translating the patella medially. Our objective was to determine whether a patellar brace can correct patellar kinematics in patients with patellofemoral OA.
We assessed the effect of a patellar brace on three-dimensional patellar kinematics (flexion, spin and tilt; proximal, lateral and anterior translation) at sequential, static knee postures, using a validated MRI-based method, in 19 patients with radiographic lateral patellofemoral OA. Differences in kinematics between un-braced and braced conditions were assessed in the unloaded and loaded knee (15% bodyweight load) using hierarchical linear random-effects models. Random slope and quadratic terms were included in the model when significant (p<0.05).
Bracing with load caused the patellae to translate 0.46 mm medially (p<0.001), tilt 1.17° medially (p<0.001), spin 0.62° externally (p=0.012) and translate 1.09 mm distally (p<0.001) and 0.47 mm anteriorly (p<0.001) over the range of knee flexion angles studied. Bracing also caused the patellae to extend in early angles of knee flexion (p<0.001). The brace caused similar trends for the unloaded condition, though magnitudes of the changes varied.
Bracing changed patellar kinematics, but these changes did not appear large enough to be clinically meaningful because no reduction in pain was observed in the parent study.
Patella; patellofemoral; osteoarthritis; brace; kinematics; MRI
The objective is to evaluate the geometric parameters of vertebral bodies and intervertebral discs in spinal segments adjacent to spondylolysis and spondylolisthesis. This pilot cross-sectional study was an ancillary project to the Framingham Heart Study. The presence of spondylolysis and spondylolisthesis as well as measurements of spinal geometry were identified on CT imaging of 188 individuals. Spinal geometry measurements included lordosis angle, wedging of each lumbar vertebra and intervertebral disc. Last measurements were used to calculate ΣB, the sum of the lumbar L1–L5 body wedge angles; and ΣD, the sum of the lumbar L1–L5 intervertebral disc angles. Using Wilcoxon–Mann–Whitney test we compared the geometric parameters between individuals with no pathology and ones with spondylolysis (with no listhesis) at L5 vertebra, ones with isthmic spondylolisthesis at L5–S1 level, and ones with degenerative spondylolisthesis at L5–S1 level. Spinal geometry in individuals with spondylolysis or listhesis at L5 shows three major patterns: In spondylolysis without listhesis, spinal morphology is similar to that of healthy individuals; In isthmic spondylolisthesis there is high lordosis angle, high L5 vertebral body wedging and very high L4–5 disc wedging; In degenerative spondylolisthesis, spinal morphology shows more lordotic wedging of the L5 vertebral body, and less lordotic wedging of intervertebral discs. In conclusion, there are unique geometrical features of the vertebrae and discs in spondylolysis or listhesis. These findings need to be reproduced in larger scale study.
Spondylolysis; Isthmic spondylolisthesis; Degenerative spondylolisthesis; Spine; Intervertebral disc; Vertebral body
Genome-wide association studies have identified genetic markers in kallikrein-related peptidase 3 (KLK3) associated with prostate cancer. However, some of these markers are also associated with prostate-specific antigen (PSA) levels, so it is unclear whether the polymorphisms are causal or if the association with risk is solely due to detection bias through PSA screening. PSA is a biologically active serine protease, cleaving insulin-like growth factor-binding protein. We examined the association of single-nucleotide polymorphisms (SNPs) in KLK3 with prostate cancer risk, disease-specific survival and pre-diagnostic PSA levels in a case–control study nested within the Physicians’ Health Study, which began in 1982, with over 27 years of follow-up. We genotyped SNPs spanning the entire KLK3 locus to capture common variation at high resolution. Six polymorphisms were significantly associated with prostate cancer incidence (P < 0.05); the odds ratios per minor allele ranged from 0.88 to 0.73. For four of these, the odds ratios were lower when restricting to cases diagnosed in the pre-PSA screening era (before 1989). The four alleles significantly associated with lower PSA levels were also associated with lower prostate cancer risk. KLK3 variants were not significantly associated with stage at diagnosis, risk of lethal cancer or survival. Our results suggest that detection bias due to the association of KLK3 variants with PSA levels cannot completely explain the association with prostate cancer risk. Understanding the mechanism by which genetic variation in KLK3 affects prostate cancer risk has important implications for study of the biological role of PSA in prostate tumorigenesis.
The goal of this systematic review was to report the responsiveness to change and reliability of conventional radiographic joint space width (JSW) measurement.
We searched the PubMed and Embase databases using the following search criteria: (osteoarthritis [MeSH]) AND (knee) AND (x-ray OR radiography OR diagnostic imaging OR radiology OR disease progression) AND (joint space OR JSW or disease progression). We assessed responsiveness by calculating the standardized response mean (SRM). We assessed reliability using intra- and inter-reader intra-class correlation (ICC) and coefficient of variation (CV). Random-effects models were used to pool results from multiple studies. Results were stratified by study duration, design, techniques of obtaining radiographs, and measurement method.
We identified 998 articles using the search terms. Of these, 32 articles (43 estimates) reported data on responsiveness of JSW measurement and 24 (50 estimates) articles reported data on measures of reliability. The overall pooled SRM was 0.33 (95% CI: 0.26, 0.41). Responsiveness of change in JSW measurement was improved substantially in studies of greater than 2 years duration (0.57). Further stratifying this result in studies of greater than two years duration, radiographs obtained with the knee in a flexed position yielded an SRM of 0.71. Pooled intra-reader ICC was estimated at 0.97 (95% CI: 0.92, 1.00) and the intra-reader CV estimated at 3.0 (95% CI: 2.0, 4.0). Pooled inter-reader ICC was estimated at 0.93 (95% CI: 0.86, 0.99) and the inter-reader CV estimated at 3.4% (95% CI: 1.3%, 5.5%).
Measurement of JSW obtained from radiographs in persons with knee is reliable. These data will be useful to clinicians who are planning RCTs where the change in minimum JSW is the outcome of interest.
knee osteoarthritis; x-ray; radiograph; responsiveness; reliability; standardized response mean
One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent SNP markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer and age.
We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.
The best risk model (C-statistic=0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P=0.009), with highest accuracy in men younger than 60 years (C-statistic=0.679). The absolute ten-year risk for 50-year old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile).
Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from PSA screening.
Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited.
Prostate cancer; polymorphism; risk prediction model
Dietary intake of one-carbon nutrients (methyl donors) and germline variants in the one-carbon metabolism genes may influence global DNA methylation level and methylation in promoter CpG islands. In this study, we evaluated the relationship between single nucleotide polymorphisms (SNPs) in the one-carbon metabolism pathway and DNA methylation status in colorectal cancer. Utilizing 182 colorectal cancers cases in two prospective cohort studies, we determined the CpG island methylator phenotype (CIMP) status on eight CIMP-specific promoters and measured LINE-1 methylation level that correlates well with genome-wide DNA methylation level. We genotyped 23 nonsynonymous SNPs in the one-carbon metabolism genes using buffy coat DNA. Most of the 23 SNPs in the one-carbon metabolism pathway were not significantly associated with CIMP-high status (≥6/8 methylated promoters). However, the MTHFR 429 Ala/Ala variant (rs1801131) and the TCN2 259 Arg/Arg variant (rs1801198) were associated with CIMP-high status (MTHFR 429 multivariate odds ratio (MV OR) = 7.56; 95% confidence interval (CI), 1.32–43.3; p trend = 0.10; TCN2 259 Arg/Arg variant MV OR = 3.82; 95% CI, 1.02–14.4; p trend = 0.06). The one-carbon metabolism genotypes were not significantly associated with LINE-1 methylation, although there were modest differences in mean LINE-1 methylation levels between certain genotypes. Collectively, these exploratory data provide suggestive evidence for the association of MTHFR 429 Ala/Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer.
SNP; One-carbon metabolism; Colorectal cancer; CIMP; DNA methylation
To determine whether older adults (age≥60 years) experience less improvement in disability and pain with nonsurgical treatment of lumbar disk herniation (LDH), as compared to younger adults (age<60 years).
Prospective longitudinal comparative cohort study.
Outpatient specialty spine clinic
133 consecutive patients with radicular pain and MR-confirmed acute LDH (89 younger adults and 44 older adults).
Nonsurgical treatment tailored to the individual patient.
Patient-reported disability on the Oswestry Disability Index (ODI), leg pain intensity, and back pain intensity were recorded at baseline, 1, 3, and 6 months. The primary outcome was the ODI change score at 6 months. Secondary longitudinal analyses examined rates of change over the follow-up period.
Older adults demonstrated improvements in ODI(range 0-100) and pain intensity(range 0-10) with nonsurgical treatment that were not significantly different from those seen in younger adults at 6 month follow-up, either with or without adjustment for potential confounders. Adjusted mean improvements in older adults as compared to younger adults were 31 vs. 33 (p=0.63) for ODI, 4.5 vs. 4.5 (p=0.99) for leg pain, and 2.4 vs. 2.7 for back pain (p=0.69). A greater amount of the total improvement in leg pain and back pain in older adults was noted in the first month of follow-up, as compared to younger adults.
These preliminary findings suggest that the outcomes of LDH with nonsurgical treatment were not worse in older adults (age≥60 years) as compared to younger adults (age<60 years). Future research is warranted to examine nonsurgical treatment for LDH in older adults.
herniation; Iitervertebral disk displacement; geriatrics; outcomes
Genome-wide association studies on pigmentary phenotypes provide a pool of candidate genetic markers for skin cancer risk. The SNPs identified from a genome-wide association study of natural hair color were assessed for associations with the risk of three types of skin cancer simultaneously in a nested case-control study within the Nurses’ Health Study (218 melanoma, 285 squamous cell carcinoma/SCC, and 300 basal cell carcinoma/BCC cases, and 870 common controls). Along with two known pigmentation loci, MC1R and OCA2, the IRF4 rs12203592 T allele was associated with an increased risk of each type of skin cancer (p value, 6.6×10−4 for melanoma, 7.0×10−7 for SCC, and 0.04 for BCC). This association was further replicated in additional samples (190 melanoma, 252 SCC, and 634 common controls). The p value in the replication set was 0.03 for melanoma and 4.2×10−3 for SCC. The risk of BCC was replicated in an independent set of 213 cases and 718 controls (p value, 0.02). The combined results showed that the association with SCC reached the genome-wide significance level (odds ratio (OR) for additive model=1.61, 95%CI, 1.36–1.91, p=3.2×10−8). The OR was 1.49 for melanoma (95%CI, 1.23–1.80; p=4.5×10−5), and 1.32 for BCC (95%CI, 1.11–1.57; p=1.6×10−3). Given that the T allele was demonstrated previously to be associated with increased expression of IRF4 locus, further studies are warranted to elucidate the role of the IRF4 gene in human pigmentation and skin cancer development.
Obesity and knee osteoarthritis are among the most frequent chronic conditions affecting Americans aged 50 to 84 years.
To estimate quality-adjusted life-years lost due to obesity and knee osteoarthritis and health benefits of reducing obesity prevalence to levels observed a decade ago.
The U.S. Census and obesity data from national data sources were combined with estimated prevalence of symptomatic knee osteoarthritis to assign persons aged 50 to 84 years to 4 subpopulations: nonobese without knee osteoarthritis (reference group), nonobese with knee osteoarthritis, obese without knee osteoarthritis, and obese with knee osteoarthritis. The Osteoarthritis Policy Model, a computer simulation model of knee osteoarthritis and obesity, was used to estimate quality-adjusted life-year losses due to knee osteoarthritis and obesity in comparison with the reference group.
U.S. population aged 50 to 84 years.
Quality-adjusted life-years lost owing to knee osteoarthritis and obesity.
Estimated total losses of per-person quality-adjusted life-years ranged from 1.857 in nonobese persons with knee osteoarthritis to 3.501 for persons affected by both conditions, resulting in a total of 86.0 million quality-adjusted life-years lost due to obesity, knee osteoarthritis, or both. Quality-adjusted life-years lost due to knee osteoarthritis and/or obesity represent 10% to 25% of the remaining quality-adjusted survival of persons aged 50 to 84 years. Hispanic and black women had disproportionately high losses. Model findings suggested that reversing obesity prevalence to levels seen 10 years ago would avert 178 071 cases of coronary heart disease, 889 872 cases of diabetes, and 111 206 total knee replacements. Such a reduction in obesity would increase the quantity of life by 6 318 030 years and improve life expectancy by 7 812 120 quality-adjusted years in U.S. adults aged 50 to 84 years.
Comorbidity incidences were derived from prevalence estimates on the basis of life expectancy of the general population, potentially resulting in conservative underestimates. Calibration analyses were conducted to ensure comparability of model-based projections and data from external sources.
The number of quality-adjusted life-years lost owing to knee osteoarthritis and obesity seems to be substantial, with black and Hispanic women experiencing disproportionate losses. Reducing mean body mass index to the levels observed a decade ago in this population would yield substantial health benefits.
Primary Funding Source
The National Institutes of Health and the Arthritis Foundation.
To evaluate how the reading of knee radiographs by site investigators differs from that by an expert musculoskeletal radiologist who trained and validated them in a multicenter knee osteoarthritis (OA) study.
Materials and methods
A subset of participants from the Osteoarthritis Initiative progression cohort was studied. Osteophytes and joint space narrowing (JSN) were evaluated using Kellgren-Lawrence (KL) and Osteoarthritis Research Society International (OARSI) grading. Radiographs were read by site investigators, who received training and validation of their competence by an expert musculoskeletal radiologist. Radiographs were re-read by this radiologist, who acted as a central reader. For KL and OARSI grading of osteophytes, discrepancies between two readings were adjudicated by another expert reader.
Radiographs from 96 subjects (49 women) and 192 knees (138 KL grade≥2) were included. The site reading showed moderate agreement for KL grading overall (kappa=0.52) and for KL≥2 (i.e., radiographic diagnosis of “definite OA”; kappa=0.41). For OARSI grading, the site reading showed substantial agreement for lateral and medial JSN (kappa=0.65 and 0.71), but only fair agreement for osteophytes (kappa=0.37). For KL grading, the adjudicator’s reading showed substantial agreement with the centralized reading (kappa=0.62), but only slight agreement with the site reading (kappa=0.10).
Site investigators over-graded osteophytes compared to the central reader and the adjudicator. Different thresholds for scoring of JSN exist even between experts. Our results suggest that research studies using radiographic grading of OA should use a centralized reader for all grading.
Osteoarthritis; Radiography; X-ray; Knee; Centralized reading
This narrative review outlines the work done in other fields with regards biomarker validation and qualification and the lessons that we may learn from this experience. Defining a universally agreed upon path for biomarker validation and qualification is urgently needed to circumvent many of the hurdles faced in OA therapeutic development irrespective of whether we are discussing biochemical markers, imaging markers or other measures. This review proposes a path that may be suitable for osteoarthritis and poses some logical next steps that will take us in this direction.
Osteoarthritis; biomarkers; imaging; biochemical marker; validation; qualification; intervention; surrogate
Cross-sectional study with prospective recruitment.
To determine the accuracy of the physical examination for the diagnosis of midlumbar nerve root impingement (L2, L3, or L4), low lumbar nerve root impingement (L5 or S1) and level-specific lumbar nerve root impingement on magnetic resonance imaging (MRI), using individual tests and combinations of tests.
Summary of Background Data
The sensitivity and specificity of the physical examination for the localization of nerve root impingement has not been previously studied.
Sensitivities, specificities and LRs were calculated for the ability of individual tests and test combinations to predict the presence or absence of nerve root impingement at midlumbar, low lumbar, and specific nerve root levels.
LRs ≥5.0 indicate moderate to large changes from pre-test probability of nerve root impingement to post-test probability. For the diagnosis of midlumbar impingement, the femoral stretch test (FST), crossed femoral stretch test (CFST), medial ankle pinprick sensation, and patellar reflex testing demonstrated LRs ≥5.0 (LR ∞). LRs ≥5.0 were seen with the combinations of FST and either patellar reflex testing (LR 7.0; 95% CI 2.3–21), or the sit-to-stand test (LR ∞). For the diagnosis of low lumbar impingement, the Achilles reflex test demonstrated a LR ≥5.0 (LR 7.1; CI 0.96–53); test combinations did not increase LRs. For the diagnosis of level-specific impingement, LRs ≥5.0 were seen for anterior thigh sensation at L2 (LR 13; 95% CI 1.8–87); FST at L3 (LR 5.7 ; 95% CI 2.3–4.4); patellar reflex testing (LR 7.7; 95% CI 1.7–35), medial ankle sensation (LR ∞), or CFST (LR 13; 95% CI 1.8–87) at L4; and hip abductor strength at L5(LR 11; 95% CI 1.3–84). Test combinations increased LRs for level-specific root impingement at the L4 level only.
Individual physical examination tests may provide clinical information which substantially alters the likelihood that midlumbar impingement, low lumbar impingement, or level-specific impingement is present. Test combinations improve diagnostic accuracy for midlumbar impingement.