Radiomics-Based Machine Learning for Outcome Prediction in a Multicenter Phase II Study of Programmed Death-Ligand 1 Inhibition Immunotherapy for Glioblastoma.

BACKGROUND AND PURPOSE: Imaging assessment of an immunotherapy response in glioblastoma is challenging due to overlap in the appearance of treatment-related changes with tumor progression. Our purpose was to determine whether MR imaging radiomics-based machine learning can predict progression-free survival and overall survival in patients with glioblastoma on programmed death-ligand 1 inhibition immunotherapy. MATERIALS AND METHODS: Post hoc analysis was performed of a multicenter trial on the efficacy of durvalumab in glioblastoma (n = 113). Radiomics tumor features on pretreatment and first on-treatment time point MR imaging were extracted. The random survival forest algorithm was applied to clinical and radiomics features from pretreatment and first on-treatment MR imaging from a subset of trial sites (n = 60-74) to train a model to predict long overall survival and progression-free survival and was tested externally on data from the remaining sites (n = 29-43). Model performance was assessed using the concordance index and dynamic area under the curve from different time points. RESULTS: The mean age was 55.2 (SD, 11.5) years, and 69% of patients were male. Pretreatment MR imaging features had a poor predictive value for overall survival and progression-free survival (concordance index = 0.472-0.524). First on-treatment MR imaging features had high predictive value for overall survival (concordance index = 0.692-0.750) and progression-free survival (concordance index = 0.680-0.715). CONCLUSIONS: A radiomics-based machine learning model from first on-treatment MR imaging predicts survival in patients with glioblastoma on programmed death-ligand 1 inhibition immunotherapy.

Complete Stokes vector analysis with a compact, portable rotating waveplate polarimeter.

Accurate calibration of polarization-dependent optical elements is often necessary in optics experiments. A versatile polarimeter device to measure the polarization state of light is a valuable tool in these experiments. Here, we report a rotating waveplate-based polarimeter capable of complete Stokes vector analysis of collimated light. Calibration of the device allows accurate measurements over a range of wavelengths, with a bandwidth of >30 nm in this implementation. A photo-interrupter trigger system supplies the phase information necessary for full determination of the Stokes vector. An Arduino microcontroller performs rapid analysis and displays the results on a liquid crystal display. The Arduino can also be interfaced with a computer to store time series of Stokes vectors. The optical measurement apparatus of the polarimeter is compact and can be placed anywhere on an optical table on a single standard post. The components to construct the device are only a fraction of the cost of commercially available devices, while the accuracy and precision of the measurements are of the same order of magnitude.

Lewisite Metabolites in Urine by Solid Phase Extraction-Dual Column Reversed-Phase Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry.

Lewisite (2-chlorovinyldichloroarsine) is a chemical warfare agent developed during World War I. A quantitative method using solid phase extraction (SPE) followed by dual column liquid chromatography (LC)-isotope dilution tandem mass spectrometry (MS-MS) was developed for the determination of (2-chlorovinyl)arsonic acid (CVAOA), a metabolite of Lewisite, in human urine. The sample was treated with hydrogen peroxide to oxidize any (2-chlorovinyl)arsonous acid (CVAA) that remained in the trivalent arsenic oxidation state. There was 1.19% (arsenic purity) of bis-(2-chlorovinyl)arsinic acid (BCVAOA), a minor Lewisite metabolite, in the stock CVAA material. The high-throughput method qualitatively assessed BCVAOA simultaneously utilizing normal-phase silica SPE followed by reversed-phase C18 LC for an orthogonal separation. The chromatographic method results in a 5.8-min cycle time with adequate retention (k' = 2.4) of CVAOA. The mass spectrometer was operated in positive electrospray ionization mode with quantitative m/z 186.9→61.0 and confirmation 186.9→91.0 mass transitions. This selective method demonstrated linearity, accuracy and reproducibility for the clinically relevant calibration range (25-3,200 µg/L as CVAA). The method detection limit was 3.3 µg/L as CVAA from a 10 µL injection. This LC-MS-MS emergency response method has a throughput of >240 samples (2.5 extracted 96-well plates) per day.

Monitoring HPV type-specific prevalence over time through clinic-based surveillance: a perspective on vaccine effectiveness.

We investigated the feasibility of monitoring trends in prevalence of vaccine-preventable human papillomavirus (HPV) types in different clinic populations. We collected cervical specimens from women presenting to family planning, primary care, and sexually transmitted disease (STD) clinics for routine pap smears in five US cities during 2003-2005. We performed HPV genotyping and calculated annual type-specific prevalences; pre-vaccine era prevalence was highest for HPV 16 (6.0; 95% confidence interval [CI] 5.5-6.6%) and annual prevalences for vaccine-preventable types were stable, with few exceptions, after controlling for clinic type, age group, and city. With sufficient sample size and stable population characteristics, clinic-based surveillance systems can contribute to monitoring HPV vaccine impact in the cervical screening population.

Resonance fluorescence from a coherently driven semiconductor quantum dot in a cavity.

We show that resonance fluorescence, i.e., the resonant emission of a coherently driven two-level system, can be realized with a semiconductor quantum dot. The dot is embedded in a planar optical microcavity and excited in a waveguide mode so as to discriminate its emission from residual laser scattering. The transition from the weak to the strong excitation regime is characterized by the emergence of oscillations in the first-order correlation function of the fluorescence, g(tau), as measured by interferometry. The measurements correspond to a Mollow triplet with a Rabi splitting of up to 13.3 microeV. Second-order correlation measurements further confirm nonclassical light emission.

Patterns and predictors of the breast cancer detection methods in women under 45 years of age (United States).

OBJECTIVES: Few studies have examined methods by which breast cancers are detected, and only one study has been published on predictors of those methods. This study examined patterns and predictors of breast cancer detection methods during 1990-1992 among women age 20-44. METHODS: In-person interview and medical record data were obtained during a population-based case-control study of 1619 women newly diagnosed with breast cancer in three areas of the United States (US). RESULTS: Seventy-one percent of the cancers were identified by self-detection, 9% by routine clinical breast exam (CBE), and 20% by routine mammography. Cancers detected by mammography and CBE, but not those detected by breast self-exam, were much more likely to be early-stage. Detection by mammography increased with age, and a history of mammography use was associated with detection by mammography or CBE. Several commonly studied predictors of screening utilization in the US population were associated with CBE detection, but were less clearly related to or unrelated to mammography detection. CONCLUSION: Findings suggest that, during the 1990s in the US, most breast cancers among women under age 45, including those age 40-44, were self-detected. Few factors other than age and prior screening are verified predictors of method of breast cancer detection.

Agricultural exposure history among African-American farmers in Georgia.

Agricultural exposures differ across the United States by region, calendar time period, and agricultural practice, but most of the published literature focuses on white men in the Midwest. A pilot study was conducted to explore the breadth and diversity of farming practices over time among African-American farmers in Georgia whose exposures may differ in important ways. Using a comprehensive life events calendar questionnaire, 17 male African-American farmers aged 36 to 86 yr residing in southeastern Georgia were interviewed regarding their agricultural history in July 1997. Most men (15/17) reported working on multiple farms in their lifetime; 3 men worked on 5 different farms during their lifetime. These farmers reported using more chemicals during their lifetime than farmers in the Midwest. Used motor oil was the most frequently reported insecticide applied to animals; this apparently common practice has not been described in the literature and should be better understood since its use may result in dermal exposure to polyaromatic hydrocarbons. Better characterization of regionally specific farming history and individual farming practices will facilitate studies of the health effects of farming.

Comparison of telephone sampling and area sampling: response rates and within-household coverage.

Random digit dialing is used frequently in epidemiologic case-control studies to select population-based controls, even when both cases and controls are interviewed face-to-face. However, concerns persist about the potential biases of random digit dialing, particularly given its generally lower response rates. In an Atlanta, Georgia, case-control study of breast cancer among women aged 20-54 years, all of whom were interviewed face-to-face, two statistically independent control groups were compared: those obtained through random digit dialing (n = 652) and those obtained through area probability sampling (n = 640). The household screening rate was significantly higher for the area sample, by 5.5%. Interview response rates were comparable. The telephone sample estimated a significantly larger percentage (by approximately 7%) of households to have no age-eligible women. Both control groups, appropriately weighted, had characteristics similar to US Census demographic characteristics for Atlanta women, except that respondents in both control groups were more educated and more likely to be married. The authors conclude that households contacted through random digit dialing are somewhat less likely to participate in the household screening process, and if they are cooperative, some households may not disclose that age-eligible women reside therein. Investigators need to develop improved methods for screening and enumerating household members in random digit dialing surveys that target a specific subpopulation, such as women.

Validation of the American Cancer Society Cancer Prevention Study II Nutrition Survey Cohort Food Frequency Questionnaire.

We assessed the validity and reproducibility of a self-administered 68-item food frequency questionnaire completed in 1992-1993 by approximately 185,000 adults. Four hundred forty-one participants completed four 24-hour dietary recall interviews over a 1-year period and a repeat administration of the food frequency questionnaire. For 20 nutrients and 10 food groups, measured nutrient intakes, but not food group intakes, were consistently lower by food frequency questionnaire than by recall. Energy-adjusted, attenuation-corrected Pearson validity correlations ranged from 0.12 to 0.80, with a median of 0.58. Reproducibility measures were generally high, with a median of 0.69. The food frequency questionnaire performed similarly to food frequency questionnaires used in other cohort studies, indicating similar ability to examine diet-disease relations.

Use of a life events calendar approach to elicit occupational history from farmers.

BACKGROUND: Precise and valid exposure assessment is generally the primary challenge in retrospective occupational epidemiology studies, particularly when the only available method for exposure characterization is a personal interview. Agricultural workers may represent a particular challenge; for example, whereas many farmers have worked from childhood at the same location, raising the same crops and animals, they may have used different equipment, chemicals, and protective gear over time. One method to assist in recall is the "life events calendar," a cognitive tool based on the subject's own life history to help anchor occupational activities in time. METHODS: Unstructured interviews of farmers, focus groups, and pilot interviews among rural men, primarily African-Americans, were conducted to create a questionnaire for obtaining farm history information within the context of personal life events. RESULTS: Farmers used both personal events and national events (as well as events relating directly to farming) to recall their activities. These subjects had extensive history of farming (10-75 years) and chemical use (median lifetime chemicals = 13). CONCLUSION: The life events calendar provided a useful tool to facilitate the recall of a lifetime of agricultural activity. Life events calendars are useful additions to the tools available for retrospective occupational exposure assessment.

Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes.

Blood samples were analyzed for GSH and GSH redox state in 40 age-related macular degeneration (ARMD) patients (> 60 y), 33 non-ARMD diabetic patients (> 60 years), 27 similarly aged non-ARMD and nondiabetic individuals (> 60 years), and 19 younger individuals (< 60 years) without ARMD or diabetes. Results showed a significantly lower plasma GSH in older individuals (ARMD, diabetes, and controls) than in younger individuals (p < .01). Total GSH (GSHt) obtained following treatment with dithiothreitol was significantly lower only in diabetic cases (p < .05) but also approached significance for ARMD cases (p = .089). Estimation of redox potential indicated that the plasma GSH pool is considerably more oxidized in all of the older groups. Analyses of whole blood GSH showed that GSH was significantly lower in diabetic cases compared to the other groups, but did not reveal any difference associated with age or ARMD. In contrast, GSSG in whole blood was significantly higher in the older groups compared to the younger controls. The results suggest that in studies of age-related pathologies, oxidation of GSH may be a more important parameter than a decline in pool size, while in specific pathologies such as diabetes, both oxidation and a decline in pool size may be important.

Energy intake and net weight gain in pregnant women according to body mass index (BMI) status.

OBJECTIVE: To investigate whether body mass index (BMI) is related to energy intake during pregnancy, and whether BMI, energy intake and other factors are related to net weight gain. DESIGN: Longitudinal, duration of pregnancy. SUBJECTS: 156 healthy pregnant women residing in Quedlinburg county, Germany. METHODS: Weighed 7 d food records and standardized anthropometric measures in the first, second and third trimester. The analysis of variance (ANOVA) statistical technique was used to analyze differences in energy intake, net weight gain and birthweight across BMI groups, and the Cochran-Mantel Haenszel test was used to analyze food group intake by BMI group. RESULTS: Women at the highest level of BMI were significantly less often in the high energy intake category than women at the medium or low level of BMI (15% vs 36% and 48%). Net weight gain during pregnancy was independently influenced by BMI status and energy intake. Women at the highest level of BMI gained significantly less weight (4.2 kg) from first to third trimester than women at the medium or low levels of BMI (weight gains of 6.2 kg and 5.9 kg, respectively). Women with a low daily energy intake gained 4.6 kg during pregnancy, while women with medium and high energy intakes gained 6.0 kg and 6.1 kg, respectively. Examination of net weight gain simultaneously across BMI and parity groups revealed a much lower net weight gain among multigravid women at the highest BMI level (3.3 kg). Primigravid high BMI women, in contrast, gained 6.9 kg, whereas multigravid and primigravid women at medium and low BMI levels gained average of 4.8 kg and 6.5 kg, respectively. The mean birth weight in the three BMI groups did not differ and was not influenced by age, marital status, education, parity or smoking. CONCLUSION: Because other studies have shown that weight gain during pregnancy increases the risk of subsequent overweight, multigravid high BMI women may prevent an increased weight retention after pregnancy due to lower weight gain in the current gestation. A lower caloric diet may help to accomplish a lower weight gain during pregnancy in overweight women without increased risk of low birth weight infants. These findings indicate further investigation of the associations between BMI, parity and caloric intake during pregnancy are needed to increase understanding of factors affecting subsequent weight gain.

The NIMH Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study: background and methodology.

OBJECTIVE: A collaborative study was conducted to develop methods for surveys of mental disorder and service utilization in unscreened population-based samples of children and adolescents. METHOD: Probability household samples of youths 9 through 17 years of age were selected at four sites and interviews were conducted with a total of 1,285 pairs of youths and their adult caretakers in their homes. Lay interviewers administered a computer-assisted version of the NIMH Diagnostic Interview Schedule for Children Version 2.3 and structured interviews to assess demographic variables, functional impairment, risk factors, service utilization, and barriers to service utilization. RESULTS: More than 7,500 households were enumerated at four sites, with enumeration response rates above 99%. Across sites, 84% of eligible youth-caretaker pairs were interviewed for about 2 hours each. Ninety-five percent of both youths and caretakers found the interview to be acceptable enough to recommend to a friend. CONCLUSIONS: These findings indicate that large-scale epidemiological surveys of mental disorders and mental health service use involving lengthy interviews in the homes of unscreened population-based samples of youths and their adult caretakers are acceptable to the community and can achieve good response rates. The other reports in this Special Section address the reliability and validity of the various survey instruments and other key findings.

Epidemiologic studies of antioxidants and cancer in humans.

To assess whether antioxidants may reduce the risk of cancer, we reviewed the epidemiologic literature from 1985 through 1993. We assessed the separate relationships of three antioxidants (carotenoids, vitamin C, and vitamin E) with six sites of cancer (lung, upper aerodigestive tract, uterine cervix, colon, breast, prostate). This review was limited to dietary intake or serum nutrient studies that met a predefined set of methodologic standards. We judged the evidence in support of causal relationships based upon consistency of results across studies, strength of association, and evidence of a dose-response relationship. The data concerning carotenoids and lung cancer risk were most consistent (protection found in 4 of 8 diet studies and 5 of 6 serum studies), with strong associations that tended to follow a dose-response pattern. For lung cancer, there was weaker evidence of protection from vitamin C (2 of 6 diet studies) and vitamin E (3 of 4 serum studies). For upper aerodigestive tract cancers (oral cavity, pharynx, or larynx), there was evidence of a protective effect of carotenoids (3 of 4 diet studies) and vitamin C (4 of 5 diet studies). For cancer of the uterine cervix, we found suggestive evidence of protection from vitamin C (4 of 5 diet studies) and perhaps carotenoids (2 of 5 diet studies). For cancers of the colon, breast, and prostate, the current data do not support a protective effect of antioxidants. More definite conclusions about the benefits of antioxidants in cancer prevention will be derived from on-going intervention trials.

Increasing the accuracy of the Expanded Programme on Immunization's cluster survey design.

The Expanded Programme on Immunization (EPI) of the World Health Organization developed a cluster survey design for the rapid assessment of children's vaccination coverage in developing countries. Because of its simplicity and familiarity, the EPI methodology has been used for additional purposes, including the detection of relatively small changes in vaccination coverage levels that are already high and the estimation of other population parameters when moderate accuracy is required. This article suggests techniques for improving the accuracy of the EPI cluster survey method, including (a) segmenting sample clusters, if necessary, so that reasonably sized areas can be counted, mapped, and listed; (b) selecting an equal probability sample of housing units within a cluster; (c) selecting a fixed number of housing units per sample cluster; and (d) performing weighted analyses. These procedures will produce accurate estimators and corresponding standard errors in EPI cluster surveys.

Dietary glutathione intake and the risk of oral and pharyngeal cancer.

Glutathione, a tripeptide found in a variety of foods, may function as an anticarcinogen by acting as an antioxidant and by binding with cellular mutagens. The association between dietary glutathione intake and risk of oral and pharyngeal cancer was investigated using data from 1,830 white participants (855 cases and 975 controls) in a population-based case-control study conducted in New Jersey; metropolitan Atlanta, Georgia; Los Angeles County, California; and Santa Clara and San Mateo counties, south of San Francisco-Oakland, California, during 1984-1985. The estimated relative risk of cancer among people with the highest quartile of glutathione intake from all sources was 0.5 (95% confidence interval 0.3-0.7). When analyzed by dietary source, however, glutathione intakes derived from all vegetables and from meat were not related to risk of cancer. Only glutathione derived from fruit and from vegetables commonly consumed raw was associated with reduced oral cancer risk. Relative to the lowest level of combined intake of fruit and of fruit-derived glutathione, risk of cancer decreased slightly with increasing intake of fruit glutathione. This analysis was limited, however, by the small numbers of subjects with extreme combinations of intakes. Further studies are needed to distinguish the potential effect of glutathione from that of fruit and raw vegetables per se or from the influence of other constituents in these foods.

Dietary glutathione intake in humans and the relationship between intake and plasma total glutathione level.

Glutathione may function as an anticarcinogen by acting as an antioxidant or by binding with cellular mutagens. Orally administered glutathione increases plasma glutathione levels, and plasma glutathione is also synthesized in the liver. To investigate the associations between glutathione intake and plasma glutathione level, we compared dietary intake estimates from food frequency questionnaire data and measured concentrations of plasma total glutathione and other serum antioxidants in 69 white men and women. Daily glutathione intake ranged from 13.0 to 109.9 mg (mean 34.8 mg). Fruits and vegetables were found to contribute over 50% of usual dietary glutathione intake, whereas meats contributed less than 25%. Small negative correlations were observed between dietary and plasma glutathione and, although they were usually not statistically significant, they were generally consistent by different time periods of dietary intake assessment. Adjustment for sex, age, caloric intake, and dietary intake of the sulfur-containing amino acids methionine and cystine did not alter the observed associations. The correlations appeared to be modified, however, by serum vitamin C concentration, with little or no association between dietary and plasma glutathione among those with lower levels of serum vitamin C and stronger negative correlations among those with higher serum vitamin C levels. These findings indicate that factors regulating plasma glutathione concentration are complex and not simply related to dietary glutathione intake or supply of precursor amino acids.

Plasma total glutathione in humans and its association with demographic and health-related factors.

The tripeptide glutathione is proposed to be protective against a number of chronic diseases including cardiovascular disease and cancer. However, there have been few studies of plasma glutathione levels in humans and in those studies the numbers of participants have been very small. In an exploratory analysis the determinants of plasma total glutathione (GSHt) were investigated in a group of 100 volunteers aged 18-61 years in Atlanta, Georgia, USA during June and July 1989. Data on demographic and health-related factors were collected by interview and plasma GSHt was measured using a recently modified laboratory method. The mean concentration of plasma GSHt for all 100 participants was 761 micrograms/l, with a standard deviation of 451 micrograms/l, a range of 86-2889 micrograms/l and a median of 649 micrograms/l. Men had significantly higher levels of plasma GSHt than women (924 v. 692 micrograms/l; P = 0.006). Seventh-day Adventists participating in the present study had higher plasma GSHt levels than other subgroups defined by race and/or religion. Among Seventh-day Adventists consumption of a vegetarian diet was associated with increased plasma GSHt concentration (P = 0.002). Plasma GSHt levels also appeared to vary by race, but relationships with race could not be clearly disassociated from relationships with religion. Among white participants plasma GSHt concentration decreased with age in women but increased with age in men (P = 0.05). Few other factors were associated with plasma GSHt concentration, although use of oral contraceptives (P = 0.10) was somewhat associated with decreased plasma GSHt levels. These findings suggest that plasma GSHt levels may vary with several demographic and health-related attributes and support the need for further research on this potentially important disease-preventive compound.

Survival differences among older dialysis patients in the southeast.

Older end-stage renal disease (ESRD) patients treated by chronic dialysis have higher mortality in the United States than in many other countries. While increasing age, white race, male sex, and/or diabetes are considered risk factors for survival, few studies of older dialysis patients have simultaneously considered multiple predictor variables and their interactions. Using information contained in the 1982 to 1986 ESRD Network 20 database for Georgia and South Carolina, we studied hospitalizations and survival of 1,354 blacks and 965 whites who were age 60 years or older when they began dialysis therapy. Survival time was modeled using the Cox life-table regression method. Older blacks' median age at dialysis initiation was 67.4, compared with 68.7 for older whites (P = 0.001). Blacks were more likely than whites (P < 0.001) to have hypertension-related or diabetes-related ESRD. White patients experienced approximately 25% more hospitalization when adjustment was made for patient-days at risk. Separate multivariate survival models were required for patients with diabetes-related versus non-diabetes-related ESRD. Among diabetics, mortality was higher among whites and among patients who were older when they began dialysis. Among patients with non-diabetes-related ESRD, mortality was higher among patients who were older when they began dialysis, but the age effect was much stronger for white males. Our hospitalization and mortality data support the view that unmeasured severity (or frailty) differences characterize white as compared with black dialysis patients. Among non-diabetes-related ESRD patients, the age effect on survival was more severe in white males than in blacks or in white females. The high mortality we observed among older dialysis patients in Georgia and South Carolina warrants further study; the data may in part reflect patients' lower socioeconomic status compared with age, race, and sex-matched controls.