Determination Of Cut Points Research Articles

Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity

Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited. To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity. In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023. Main outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests. Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index. This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD. In this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

Predictive Value of C-Peptide Measures for Clinical Outcomes of β-Cell Replacement Therapy in Type 1 Diabetes: Report From the Collaborative Islet Transplant Registry (CITR).

To determine C-peptide measures and levels associated with positive glycemic control outcomes following islet transplant (ITx) in type 1 diabetes. We evaluated Collaborative Islet Transplant Registry (CITR) islet-alone recipients with pretransplant C-peptide <0.1 nmol/L and mean follow-up of 4.6 ± 1.1 years (n = 677). Receiver operating characteristic area under the curve (ROC-AUC) was used to evaluate the predictive value of fasting and stimulated glucose and C-peptide measures for seven primary outcomes: 1) absence of severe hypoglycemic events (ASHEs); 2) HbA1c <7.0%; 3) HbA1c <7.0% and ASHEs; 4) HbA1c ≤6.5%; 5) HbA1c ≤6.5% and ASHEs; 6) insulin independence; and 7) ASHEs, HbA1c ≤6.5%, and insulin independence (the optimal outcome). Measures with the highest ROC-AUC were selected for determination of optimal cut points. Fasting C-peptide was highly predictive for ASHE (ROC-AUC 0.906; optimal cut point 0.070 nmol/L) and the optimal outcome (ROC-AUC 0.845; optimal cut point 0.33 nmol/L). Mixed-meal tolerance test (MMTT)-stimulated C-peptide-to-glucose ratio (CPGR) outperformed both fasting and stimulated C-peptide for all outcomes except ASHE. The optimal cut point for the optimal outcome was 0.12 nmol/mmol for MMTT-stimulated CPGR and 0.97 nmol/L for MMTT-stimulated C-peptide. Fasting C-peptide reliably predicts ITx primary outcomes. MMTT-stimulated CPGR provides marginally better prediction for composite ITx outcomes, including insulin independence. In the absence of an MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal islet graft function. C-peptide targets represent excellent and easily determinable means to predict glycemic control outcomes after ITx and should be considered as potential goals of β-cell replacement.

The effect of colorization on the fetal lung heterogeneity index.

No previous studies have quantitatively assessed the effect of color tones on ultrasound texture analysis techniques. Our objective was to compare heterogeneity index (HI) between fetal lung images captured in grayscale and those same images after conversion to Ice and Sepia. Fetal lung images were obtained during medically indicated ultrasound examinations. We observed that HI is affected by the application of color tones to ultrasound images of the fetal lung. Therefore, for each type of biological tissue and color tone, determination of distinct HI nomograms and cut off points is recommended.

Establishing an Autopsy-Based Cerebrospinal Fluid Biomarker Signature in Alzheimer Disease Patients.

Featured Article: Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, et al. Cerebrospinal fluid biomarker signature in Alzheimer's Disease Neuroimaging Initiative subjects. Ann Neurol 2009;65:403-13.† At the time this work was conducted (2007 to 2008), the research use of cerebrospinal fluid (CSF) biomarker proteins linked to Alzheimer disease (AD) hallmarks—β-amyloid (Aβ) plaque load and tau pathology (Aβ1-42, t-tau, and p-tau181) —was becoming established practice amongst a number of experienced laboratories as reliable and accurate indices of brain pathology in living subjects (1–3). These studies mainly used either a widely employed ELISA methodology (4) or the newer (at the time) microbead-based biomarkers multi analyte profiling (xMAP) immunoassay format, developed by Innogenetics (now Fujirebio) (5). The data generated from more than 25 studies that used these techniques and CSF provided strong support for a more objective measurement of amyloid and tau pathology in living individuals, compared to clinical diagnosis of AD dementia (6). The clinical diagnosis of AD is only up to about 80% accurate and our 2009 study in Annals of Neurology and other studies provided the foundation for moving towards a biological basis (protein biomarker profile) for more accurate clinical diagnosis of the presence of ongoing AD brain pathology. Two populations were used in our study: (a) participants in the multicenter study, the Alzheimer's Disease Neuroimaging Initiative (ADNI; 100 patients with early AD, 196 patients with mild cognitive impairment, and 115 cognitively normal age-matched controls, all clinically diagnosed), provided CSF samples collected at 56 centers at the participants’ baseline visit, and (b) an independent population, followed at the University of Pennsylvania Alzheimer's Disease Clinical Core, of 56 autopsy-confirmed AD participants and 52 age-matched living cognitively normal controls. Besides inclusion of an ADNI-independent population for assessment of cutpoint values for each of the 3 AD biomarkers as well as for the ratios t-tau/Aβ1-42 and p-tau181/Aβ1-42, another key feature in this study was the close collaboration between an in vitro diagnostic company and a university laboratory with the aim of generating best-in-class assays for the benefit of patients, and the inclusion of autopsy diagnosis for the patients with AD, the accepted gold standard for diagnosis of this disease. This enabled (a) determination of the accuracy of prediction of AD pathology assessed by receiver operating characteristic curve (AUC) analyses, (b) determination of cutpoints for the individual proteins and their ratios, and (c) establishment of a logistic regression model that combined Aβ1-42, t-tau, and APOε4 genotype. AUC values ranged from 0.913 for CSF Aβ1-42 concentration alone up to 0.942 for the combination of Aβ1-42, t-tau, and APOε4 genotype. Importantly, the same lot of reagents was used for the analyses in both populations, thus removing lot-to-lot variability from measurement errors. At the time this work was done, it was a considerable source of variability using this “for research-use-only (RUO)” immunoassay. It was an important additional feature of this study.

207.3: Predictive Value of C-peptide Measures for Clinical Outcomes of Islet Transplantation in Type 1 Diabetes: A Report From the Collaborative Islet Transplant Registry (CITR)

CITR Investigators Introduction: Long-standing type 1 diabetes (T1D) can lead to impaired awareness of hypoglycemia and high-risk for severe hypoglycemic episodes (SHE). Islet transplantation (ITx) can restore endogenous insulin production, ameliorate glucose control, and abolish SHE. In the DCCT, a stimulated C-peptide >0.2 nmol/L was associated with lower HbA1c, reduced insulin requirements, and decreased prevalence of SHE. We set forth to determine what measures of C-peptide and levels are associated with achievement of ITx positive outcomes in T1D. Methods: Collaborative Islet Transplant Registry (CITR) Islet-Alone recipients with pre-transplant C-peptide <0.1 nmol/L and mean follow up of 4.6±1.1 years were included in the analyses (n=677). Post-transplant metabolic measures obtained from arginine stimulation test, IVGTT, OGTT, glucagon stimulation test and mixed meal stimulation test (MMTT) were evaluated. Predictive value of these measures for 7 primary outcomes of clinical ITx (i.e., absence of SHEs (ASHE); HbA1c<7.0%; HbA1c <7.0% & ASHE; HbA1c≤6.5; HbA1c≤6.5% & ASHE; insulin independence; and ASHE, HbA1c≤6.5%, and insulin independence) was assessed by area under the curve of receiver-operator characteristics curves (ROC-AUC). Measures with the highest ROC-AUC were then selected for determination of optimal cut points by ITx outcome. Results: Fasting C-peptide, MMTT stimulated C-peptide, fasting C-peptide to Glucose (Cpep/Glu) ratio, and MMTT stimulated Cpep/Glu ratio showed the highest ROC-AUCs among all measures evaluated (Table 1). Fasting C-peptide was highly predictive for ASHE (ROC-AUC = 0.9228; optimal cut point = 0.07 nmol/L), and the composite outcome of ASHE, HbA1c≤6.5%, and insulin independence (ROC-AUC = 0.8456; optimal cut point = 0.33 nmol/L) (Table 2). However, MMTT stimulated Cpep/Glu ratio outperformed both fasting and stimulated C-peptide for all outcomes except ASHE alone. Optimal cut point for the ideal composite outcome of ASHE, HbA1c≤6.5%, and insulin independence was 0.12 nmol/mmol for the MMTT stimulated Cpep/Glu ratio, and 0.97 nmol/L for MMTT stimulated C-peptide (Table 2). Discussion/Conclusion: Fasting C-peptide reliably predicts rates of ITx primary endpoints and is similar to other C-peptide measures at predicting ASHE. Although marginal endogenous fasting C-peptide is sufficient to eliminate SHEs, higher levels are required to achieve optimal ITx outcomes. The MMTT stimulated Cpep/Glu ratio provides better predictiveness for composite ITX outcomes, including insulin independence. In the absence of a MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal metabolic control in ITx T1D recipients.The CITR has been funded continuously by grants from the National Institute of Diabetes and Digestive and Kidney Diseases since 2001 (Grants 1UCHDK098086-01, 1UC4DK114839-01) to collect data on the efficacy and safety of clinical islet transplantation from US and collaborating international institutions. The Juvenile Diabetes Research Foundation provided supplemental funding for reimbursement of efforts to report data from the European and Australian sites from 2006–2015. No other sponsors have provided support to the CITR. MRR is supported in part by Public Health Service Research Grant R01 DK 091331-8. We thank all the study participants and staff.

Determination of Cutpoints for Symptom Burden in Oncology Patients Receiving Chemotherapy

ContextCutpoints can be used as a threshold for screening symptom(s) that warrant intervention(s) and for monitoring patients’ responses to these interventions. ObjectivesIn a sample of oncology patients undergoing chemotherapy, study purposes were to determine the optimal cutpoints for low, moderate, and high symptom burden and determine if these cutpoints distinguished among the symptom groups in any demographic, clinical, and stress characteristics, as well as QOL outcomes. MethodsTotal of 1329 patients completed a modified version of the Memorial Symptom Assessment Scale (38 symptoms). Using the methodology of Serlin and colleagues, cutpoints were created using symptom occurrence rates and cancer-specific quality of life (QOL) scores. Cutpoints were validated using measures of stress and resilience and a generic measure of QOL (i.e., Medical Outcomes Study Short Form 12 (SF-12)). ResultsOf the 25 possible cutpoints evaluated, the optimal cutpoint, with the largest between category F statistic, was CP8,15 (Low = 0–8, Moderate = 9–15, High = 16–38 symptoms). Percentage of patients in the Low, Moderate, and High cutpoint groups were 25.3%, 36.3%, and 38.4%, respectively. Significant differences were found among the symptom burden groups in global, cancer-specific, and cumulative life stress (i.e., Low < Moderate < High) and resilience and SF-12 (i.e., Low > Moderate > High) scores. ConclusionOur findings provide evidence for clinically meaningful cutpoints that can be used to guide symptom assessment and management. These cutpoints may be used to establish alert thresholds for electronic monitoring of symptoms in oncology patients.

Handgrip Strength, but Not 5-Meter Walk, Adds Value to a Clinical Nutrition Assessment.

Decreased physical functioning is associated with malnutrition and common in acute care patients; determining loss of function is often considered part of a comprehensive nutrition assessment. Handgrip strength (HGS) and 5-meter timed walk (5m) are functional measures used in a variety of settings. This analysis sought to determine which functional measure could be added to a hospital nutrition assessment, based on its feasibility and capacity to discriminate patient subgroups. Eligible medical patients (no delirium/dementia, admitted from community; n = 1250), recruited from 5 hospitals that participated in a previous multisite action research study, provided data on demographics, HGS, 5m, nutrition status, perceived disability, and other characteristics. Significantly more patients (z = 17.39, P < .00001) were able to complete HGS than 5m (92% versus 43%, respectively). Median HGS was 28.0 kg for men and 14.7 kg for women. Of patients who completed the 5m, mean completion time was 8.98 seconds (median, 6.79 seconds, SD = 6.59). 5m and HGS scores were significantly worse with patient-perceived disability (z = -9.56, t = 10.69, respectively; P < .0001; 95% confidence interval [CI], [7.33, 10.63]; [1.76, 3.18]). HGS was associated with nutrition status (t = 4.13, P < .001; 95% CI [2.02, 5.67]), although it showed poor validity as a single nutrition indicator. These data indicate that HGS is a more useful functional measure than 5m when added to a hospital nutrition assessment. Determination of HGS cutpoints to identify low strength in acute care patients will promote its use.

Standards of an Examination (cut points), Construction of Scenarios, Measurement of lmpacts in the Decision Making Process

The National Board of Medical Examiners (NBME®) applies rigorous examinations to determine the impact on candidates taking the United States Medical License Examination (USMLE®) for the purpose of licensing physicians in the US. UU UU These standards apply to all levels of exam development, administration and qualification. The standards apply to the following processes:• Validity of the inferences of the articles: content: the content tested must be appropriate, asking the correct questions, the format of the element, or the design of the test and the design, or the process by which the test is performed, the documentation• Accuracy of the scores: reliability, focalization, information on the cutting edge, standard errors• Determination and application of cut points: methods, modified Angoff procedure, misclassification error.The main focus is on the last standard, although the first two levels are also briefly discussed. Different methods to establish an approval standard will be discussed and the method used for USMLE will be described. Errors of misclassification are also presented and how to minimize them.

Determination of optimum medical cut points for continuous covariates in lifetime regression models

Determination of optimum medical cut points for continuous covariates in lifetime regression models

Development and validation of a cell based assay for the detection of neutralizing antibodies against recombinant insulins

Recombinant biopharmaceuticals can induce generation of anti-drug antibodies, which could potentially neutralize therapeutic drug activity. In this report, we describe development and validation of a cell-based assay for detection of neutralizing antibodies (Nab) against insulin and insulin analogues. In order to achieve clinically meaningful sensitivity the method used an early signalling event, insulin induced insulin receptor phosphorylation as the endpoint. Percentage insulin receptor phosphorylation in cell lysates was measured using ECL based ELISA. Presence of neutralizing antibodies (Nab) in samples will inhibit insulin induced receptor phosphorylation and consequently lead to a reduction in the percentage of phosphorylated insulin receptor. Additionally, usage of human insulin receptor overexpressing recombinant CHO cell line further improved the assay sensitivity by reducing the fixed drug (EC50) concentration used for induction of receptor phosphorylation. To ensure adequate free drug tolerance a pre-treatment step was introduced, where serum samples underwent acid dissociation and charcoal extraction before drug incubation. In order to distinguish ADA positive samples containing true Nab from samples containing non-antibody phosphorylation inhibitory serum factors, a confirmatory tier was integrated based on immunodepletion using protein AGL mix. Assay parameters including determination of screening and confirmatory cut-points, intra and inter assay precision, selectivity, specificity and stability were assessed during validation in accordance with recent regulatory guidelines and white papers. The advantage of selecting insulin receptor phosphorylation as assay endpoint made the assay capable of detecting Nab against insulin and insulin analogues.

Recommendations for Systematic Statistical Computation of Immunogenicity Cut Points.

Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti-drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three-tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme. Depending on a biotherapeutic's structural attributes, more characterization and testing may be appropriate. Unlike bioanalytical assays used to support the evaluation of pharmacokinetics or toxicokinetics, an important component in immunogenicity testing is the calculation of cut points for the identification (screening), confirmation (specificity), and titer assessment responses in animals and humans. Several key publications have laid an excellent foundation for statistical design and data analysis to determine immunogenicity cut points. Yet, the process for statistical determination of cut points remains a topic of active discussion by investigators who conduct immunogenicity assessments to support biotherapeutic drug development. In recent years, we have refined our statistical approach to address the challenges that have arisen due to the evolution in biotherapeutics and the analytical technologies used for quasi-quantitative detection. Based on this collective experience, we offer a simplified statistical analysis process and flow-scheme for cut point evaluations that should work in a large majority of projects to provide reliable estimates for the screening, confirmatory, and titering cut points.

International development and psychometric properties of the Child and Adolescent Trauma Screen (CATS)

BackgroundSystematic screening is a powerful means by which children and adolescents with posttraumatic stress symptoms (PTSS) can be detected. Reliable and valid measures based on current diagnostic criteria are needed. AimTo investigate the internal consistency and construct validity of the Child and Adolescent Trauma Screen (CATS) in three samples of trauma-exposed children in the US (self-reports: n=249; caregiver reports: n=267; pre-school n=190), in Germany (self-reports: n=117; caregiver reports: n=95) and in Norway (self-reports: n=109; caregiver reports: n=62). MethodInternal consistency was calculated using Cronbach's α. Convergent-discriminant validity was investigated using bivariate correlation coefficients with measures of depression, anxiety and externalizing symptoms. CFA was used to investigate the DSM-5 factor structure. ResultsIn all three language samples the 20 item symptom score of the self-report and the caregiver report proved good to excellent reliability with α ranging between .88 and .94. The convergent-discriminant validity pattern showed medium to strong correlations with measures of depression (r =.62–.82) and anxiety (r =.40–.77) and low to medium correlations with externalizing symptoms (r =−.15–.43) within informants in all language versions. Using CFA the underlying DSM-5 factor structure with four symptom clusters (re-experiencing, avoidance, negative alterations in mood and cognitions, hyperarousal) was supported (n =475 for self-report; n =424 for caregiver reports). LimitationsThe external validation of the CATS with a DSM-5 based semi-structured clinical interview and corresponding determination of cut-points is pending. ConclusionThe CATS has satisfactory psychometric properties. Clinicians may consider the CATS as a screening tool and for symptom monitoring.

Statistical approaches for the determination of cut points in anti-drug antibody bioassays

Cut points in immunogenicity assays are used to classify future specimens into anti-drug antibody (ADA) positive or negative. To determine a cut point during pre-study validation, drug-naive specimens are often analyzed on multiple microtiter plates taking sources of future variability into account, such as runs, days, analysts, gender, drug-spiked and the biological variability of un-spiked specimens themselves. Five phenomena may complicate the statistical cut point estimation: i) drug-naive specimens may contain already ADA-positives or lead to signals that erroneously appear to be ADA-positive, ii) mean differences between plates may remain after normalization of observations by negative control means, iii) experimental designs may contain several factors in a crossed or hierarchical structure, iv) low sample sizes in such complex designs lead to low power for pre-tests on distribution, outliers and variance structure, and v) the choice between normal and log-normal distribution has a serious impact on the cut point.We discuss statistical approaches to account for these complex data: i) mixture models, which can be used to analyze sets of specimens containing an unknown, possibly larger proportion of ADA-positive specimens, ii) random effects models, followed by the estimation of prediction intervals, which provide cut points while accounting for several factors, and iii) diagnostic plots, which allow the post hoc assessment of model assumptions. All methods discussed are available in the corresponding R add-on package mixADA.

Two non-parametric methods for derivation of constraints from radiotherapy dose–histogram data

Dose constraints based on histograms provide a convenient and widely-used method for informing and guiding radiotherapy treatment planning. Methods of derivation of such constraints are often poorly described. Two non-parametric methods for derivation of constraints are described and investigated in the context of determination of dose-specific cut-points—values of the free parameter (e.g., percentage volume of the irradiated organ) which best reflect resulting changes in complication incidence. A method based on receiver operating characteristic (ROC) analysis and one based on a maximally-selected standardized rank sum are described and compared using rectal toxicity data from a prostate radiotherapy trial. Multiple test corrections are applied using a free step-down resampling algorithm, which accounts for the large number of tests undertaken to search for optimal cut-points and the inherent correlation between dose–histogram points. Both methods provide consistent significant cut-point values, with the rank sum method displaying some sensitivity to the underlying data. The ROC method is simple to implement and can utilize a complication atlas, though an advantage of the rank sum method is the ability to incorporate all complication grades without the need for grade dichotomization.

Menstrual cycle characteristics in fertile women from Greenland, Poland and Ukraine exposed to perfluorinated chemicals: a cross-sectional study

Does perfluorooctane sulfonate (PFOS) and perfluorooctanate (PFOA) exposure disrupt the menstrual cyclicity? The female reproductive system may be sensitive to PFOA exposure, with longer menstrual cycle length at higher exposure. PFOS and PFOA are persistent man-made chemicals. Experimental animal studies suggest they are reproductive toxicants but epidemiological findings are inconsistent. A cross-sectional study including 1623 pregnant women from the INUENDO cohort enrolled during antenatal care visits between June 2002 and May 2004 in Greenland, Poland and Ukraine. Information on menstrual cycle characteristics was obtained by questionnaires together with a blood sample from each pregnant woman. Serum concentrations of PFOS and PFOA were measured by liquid chromatography tandem mass spectrometry. Multiple imputations were performed to account for missing data. The association between PFOS/PFOA and menstrual cycle length (short cycle: ≤24 days, long cycle: ≥32 days) and irregularities (≥7 days in difference between cycles) was analyzed using logistic regression with tertiles of exposure. Estimates are given as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Higher exposure levels of PFOA were associated with longer menstrual cycles in pooled estimates of all three countries. Compared with women in the lowest exposure tertile, the adjusted OR of long cycles was 1.8 (95% CI: 1.0; 3.3) among women in the highest tertile of PFOA exposure. No significant associations were observed between PFOS exposure and menstrual cycle characteristics. However, we observed a tendency toward more irregular cycles with higher exposure to PFOS [OR 1.7 (95% CI: 0.8; 3.5)]. The overall response rate was 45.3% with considerable variation between countries (91.3% in Greenland, 69.1% in Poland and 26.3% in Ukraine). Possible limitations in our study include varying participation rates across countries; a selected study group overrepresenting the most fertile part of the population; retrospective information on menstrual cycle characteristics; the determination of cut-points for all three outcome variables; and lacking information on some determinants of menstrual cycle characteristics, such as stress, physical activity, chronic diseases and gynecological disorders, thus confounding cannot be excluded. The generalizability of the study results is restricted to fertile women who manage to conceive and women who do not use oral contraceptives when getting pregnant or within 2 months before getting pregnant. To our knowledge only one previous epidemiological study has addressed the possible association between perfluorinated chemical exposure and menstrual disturbances. Though pointing toward different disturbances in cyclicity, both studies suggest that exposure to PFOA may affect the female reproductive function. This study contributes to the limited knowledge on effects of exposure to PFOA and PFOS on female reproductive function and suggests that the female reproductive system may be affected by environmental exposure to PFOA. Supported by a scholarship from Aarhus University Research Foundation. The collection of questionnaire data and blood samples was part of the INUENDO project supported by The European Commission (Contract no. QLK4-CT-2001-00 202), www.inuendo.dk. The Ukrainian part of the study was possible by a grant from INTAS (project 012 2205). Determination of PFOA and PFOS in serum was part of the CLEAR study (www.inuendo.dk/clear) supported by the European Commission's 7th Framework Program (FP7-ENV-2008-1-226217). No conflict of interest declared.

Actigraph GT3X: Validation and Determination of Physical Activity Intensity Cut Points

The aims of this study were: to compare energy expenditure (EE) estimated from the existing GT3X accelerometer equations and EE measured with indirect calorimetry; to define new equations for EE estimation with the GT3X in youth, adults and older people; and to define GT3X vector magnitude (VM) cut points allowing to classify PA intensity in the aforementioned age-groups. The study comprised 31 youth, 31 adults and 35 older people. Participants wore the GT3X (setup: 1-s epoch) over their right hip during 6 conditions of 10-min duration each: resting, treadmill walking/running at 3, 5, 7, and 9 km · h⁻¹, and repeated sit-stands (30 times · min⁻¹). The GT3X proved to be a good tool to predict EE in youth and adults (able to discriminate between the aforementioned conditions), but not in the elderly. We defined the following equations: for all age-groups combined, EE (METs)=2.7406+0.00056 · VM activity counts (counts · min⁻¹)-0.008542 · age (years)-0.01380 · body mass (kg); for youth, METs=1.546618+0.000658 · VM activity counts (counts · min⁻¹); for adults, METs=2.8323+0.00054 · VM activity counts (counts · min⁻¹)-0.059123 · body mass (kg)+1.4410 · gender (women=1, men=2); and for the elderly, METs=2.5878+0.00047 · VM activity counts (counts · min⁻¹)-0.6453 · gender (women=1, men=2). Activity counts derived from the VM yielded a more accurate EE estimation than those derived from the Y-axis. The GT3X represents a step forward in triaxial technology estimating EE. However, age-specific equations must be used to ensure the correct use of this device.

Correlación de la escala de somnolencia de Epworth con el diagnóstico y severidad del síndrome de apnea hipopnea obstructiva del sueño (sahos)

Introducción: diferentes publicaciones han cuestionado la utilidad de la escala de Epworth de somnolencia y sugieren falta de correlación con la severidad del SAHOS dado por el índice de apnea hipopnea y con desenlaces clínicos.Objetivos: determinar el índice de correlación del puntaje de la escala de Epworth y el índice de apnea hipopnea del sueño. Identificar el punto de corte mediante curva ROC para el puntaje de la escala y el índice de apnea hipopnea (IAH) del polisomnograma. Identificar qué variables de la escala se correlacionan mejor con el diagnóstico de SAHOS.Diseño: estudio descriptivo de corte transversal, estudio de correlación. Determinación de puntos de corte mediante curvas ROC.Materiales y métodos: se usó la base de datos de los pacientes a los que se les realizó polisomnograma basal en la Clínica de Marly desde marzo de 2005 hasta julio de 2009 y en el Hospital Universitario San Ignacio desde marzo de 2005 a febrero de 2013. Previo al procedimiento todos los pacientes fueron entrevistados por un Neumólogo especialista en sueño y se llenó una encuesta estandarizada. Mediante el programa de estadística STATA 12.0 se hallaron los datos demográficos de la población y se estudió la correlación entre IAH y el puntaje de Epworth. Igualmente, se evaluaron diferentes puntos de corte mediante la curva ROC. Se hicieron análisis parciales retirando, en un proceso secuencial, variables de la escala de Epworth para repetir los análisis, y se analizaron los diferentes grados de severidad, por separado en el IAH, para la búsqueda de correlación.Resultados: se analizaron los datos de 3.093 pacientes (46,57% mujeres), con un promedio de edad de 56,52 años. El peso promedio fue de 81,9±17,6 kg con un IMC promedio de 31,91 (± 6,54) kg/m2. El 87,78% tenía IMC mayor o igual a 25. El diagnóstico de SAHOS se realizó en 2.667 pacientes (86,23%), con un IAH de 5 o más. El IAH en promedio fue de 32,76 (± 29,05). El análisis de correlación entre el puntaje de la escala de Epworth y el IAH (Rho de Spearman) es de 0,075 (p=0,0001) lo cual indica que no hay correlación. La curva ROC no permitió elegir ningún punto de corte apropiado para la escala de Epworth en relación con el diagnóstico de SAHOS (área bajo la curva 0,52).Conclusiones: el resultado del estudio muestra que la escala de Epworth no tiene correlación con el IAH medido por polisomnograma. No se encontró algún punto de corte que muestre mejor sensibilidad ni especificidad. La valoración multidisciplinaria y la alta sospecha diagnóstica continúan siendo el mejor método para seleccionar los pacientes que deben ser llevados a estudio polisomnográfico.

Determination of Cutpoints for Low and High Number of Symptoms in Patients with Advanced Cancer

While patients with advanced cancer experience a wide range of symptoms, no work has been done to determine an optimal cutpoint for a low versus a high number of symptoms. Analytic approaches that established clinically meaningful cutpoints for the severity of cancer pain and fatigue provided the foundation for this study. The purpose of this study was to determine the optimal cutpoint for low and high numbers of symptoms using a range of potential cutpoints and to determine if those cutpoints distinguished between the two symptom groups on demographic and clinical characteristics and depression, anxiety, and quality of life (QOL). Patients with advanced cancer (n=110) completed a symptom assessment scale, and measures of depression, anxiety, and QOL. Combinations of cutpoints were tested to yield one- and two-cutpoint solutions. Using analysis of variance for QOL scores, the F-ratio that indicated the highest between-group difference was determined to be the optimal cutpoint between low and high number of symptoms. A cutpoint of ≤ 12 symptoms (i.e., 0-12 is low, 13-32 is high) was the optimal cutpoint for total number of symptoms. Significant differences in depression, anxiety, and QOL scores validated this cutpoint. Psychological symptoms had higher occurrence rates in the high symptom group. Findings suggest that a threshold exists between a low and a high number of symptoms in patients with advanced cancer. Psychological symptoms were significantly different between patients in the low versus high symptom groups and may play an important role in QOL outcomes in patients with advanced cancer.

Efficacy of Using the Japanese Version of the Asthma Control Test for Determing the Level of Asthma Control in Clinical Settings

The Asthma Control Test (ACT) is frequently used for the evaluation of asthma control in clinical care setting because it does not require the use of pulmonary function tests, which can be difficult for general practitioners to use. However, few large-scale studies have investigated the efficacy of the Japanese version ACT (J-ACT) in actual use during clinical care. The aim of this study was to analyze the efficacy of the J-ACT in a clinical care setting. Using data from a 2008 questionnaire survey including the J-ACT by the Niigata Asthma Treatment Study Group, we compared the ACT scores of 2233 patients with respect to multiple parameters, including the severity by Japanese Society of Allergology and the attack frequency. Using the definition of asthma control partially referred to Global Initiative for Asthma (GINA) guidelines from the survey data, the accuracy screening and determination of optimal ACT cutpoints were performed by retrospective analysis. Cronbach's α for the J-ACT was 0.785. Patients with more severe asthma and more frequent asthma attacks had lower ACT scores than did patients with less severe, less frequent attacks. The optimal ACT cutpoints were 24 for the controlled asthma and 20 for the uncontrolled asthma. Our study, the first large-scale investigation of the efficacy of the J-ACT, determined that this evaluation tool is highly efficacious in establishing the level of asthma control. However, the determination of accurate cutpoints for the J-ACT will require more clear definitions of asthma control in future prospective studies.

Determination and application of cut points for accelerometer-based activity counts of activities with differing intensity in pet dogs

To investigate whether an accelerometer-based activity monitor could be used in pet dogs to differentiate among and delineate the amount of time spent in activities of differing intensity. 104 dogs. For the first phase of the study, each dog (n = 104) wore an accelerometer-based activity monitor and was led through a series of standard activities (recumbency [sedentary], walking, and trotting). Receiver operating characteristic curves were generated to determine the optimal activity counts for predicting whether a dog was sedentary, walking, or trotting. For the second phase of the study, dogs (n = 99) wore an activity monitor on their collars continuously for 14 days at home; intensity of activity for each dog was classified by use of cut points determined on the basis of results obtained during the first phase of the study. Analysis of receiver operating characteristic curves indicated that there was 100% specificity and 100% sensitivity in distinguishing sedentary activity from walking activity and 92% specificity and 92% sensitivity in distinguishing trotting activity from walking activity. Analysis of data collected during the 14-day period at home indicated that dogs were sedentary most of the time (median, 87%; range, 65% to 95%). Counts recorded by an accelerometer-based activity monitor could be used to discriminate effectively among standardized activities in pet dogs. There is potential for use of the method to improve the ability of clinicians and researchers to accurately estimate a pet dog's daily energy requirement.