A simulation study of nonparametric total deviation index as a measure of agreement based on quantile regression.

Total deviation index (TDI) captures a prespecified quantile of the absolute deviation of paired observations from raters, observers, methods, assays, instruments, etc. We compare the performance of TDI using nonparametric quantile regression to the TDI assuming normality (Lin, 2000). This simulation study considers three distributions: normal, Poisson, and uniform at quantile levels of 0.8 and 0.9 for cases with and without contamination. Study endpoints include the bias of TDI estimates (compared with their respective theoretical values), standard error of TDI estimates (compared with their true simulated standard errors), and test size (compared with 0.05), and power. Nonparametric TDI using quantile regression, although it slightly underestimates and delivers slightly less power for data without contamination, works satisfactorily under all simulated cases even for moderate (say, ≥40) sample sizes. The performance of the TDI based on a quantile of 0.8 is in general superior to that of 0.9. The performances of nonparametric and parametric TDI methods are compared with a real data example. Nonparametric TDI can be very useful when the underlying distribution on the difference is not normal, especially when it has a heavy tail.

Minimum clinically important difference in medical studies.

In clinical trials, minimum clinically important difference (MCID) has attracted increasing interest as an important supportive clinical and statistical inference tool. Many estimation methods have been developed based on various intuitions, while little theoretical justification has been established. This article proposes a new estimation framework of the MCID using both diagnostic measurements and patient-reported outcomes (PROs). The framework first formulates the population-based MCID as a large margin classification problem, and then extends to the personalized MCID to allow individualized thresholding value for patients whose clinical profiles may affect their PRO responses. More importantly, the proposed estimation framework is showed to be asymptotically consistent, and a finite-sample upper bound is established for its prediction accuracy compared against the ideal MCID. The advantage of our proposed method is also demonstrated in a variety of simulated experiments as well as two phase-3 clinical trials.

A comparison model for measuring individual agreement.

This article proposes a general comparison model for assessing individual agreement of k  ≥  2 raters evaluating n subjects with m  ≥  2 replicated readings. Users can explore total-rater agreement relative to intrarater agreement where any subset of the k raters can be selected in the numerator and denominator. Users are also allowed to compare intrarater agreement among selected raters. Based on the ratio of mean squared deviations (MSDs), two comparative agreement indices, total-intra ratio (TIR) and intra-intra ratio (IIR), are proposed. The TIR is a noninferiority assessment such that the differences of individual readings from different raters cannot be inferior by a prespecified margin to the differences of the replicated readings within raters. TIR can be used whether a reference exists or not. The method used by the Food and Drug Administration (FDA) for evaluating individual bioequivalence under relative scale becomes the special case of our approach. The IIR is a classical assessment such that the precision of selected raters can be better than; equal to; or worse than that of other raters. The estimation and statistical inference of TIR and IIR are obtained through GEE methodology.

Morphological Characterization of the Polyflux 210H Hemodialysis Filter Pores.

Background. Morphological characterization of hemodialysis membranes is necessary to improve pore design. Aim. To delineate membrane pore structure of a high flux filter, Polyflux 210H. Methods. We used a Joel JSM-6010LV scanning electron microscope (SEM) and a SU6600 Hitachi field emission scanning electron microscope (FESEM) to characterize the pore and fiber morphology. The maximal diameters of selected uremic toxins were calculated using the macromolecular modeling Crystallographic Object-Oriented Toolkit (COOT) software. Results. The mean pore densities on the outermost and innermost surfaces of the membrane were 36.81% and 5.45%, respectively. The membrane exhibited a tortuous structure with poor connection between the inner and outer pores. The aperture's width in the inner surface ranged between 34 and 45 nm, which is 8.76-11.60 times larger than the estimated maximum diameter of ß2-microglobulin (3.88 nm). Conclusion. The results suggest that the diameter size of inner pore apertures is not a limiting factor to middle molecules clearance, the extremely diminished density is. Increasing inner pore density and improving channel structure are strategies to improve clearance of middle molecules.

Prognostic factors in survival of colorectal cancer patients after surgery.

OBJECTIVE: To determine the factors affecting survival, following resection of large bowel for colorectal carcinoma. METHOD: From the cancer database of a single referral institution, a total of 1090 patients who had undergone colorectal resection between 1999 and 2002 were identified. Cases with recurrent colorectal cancer or previous history of neoadjuvant chemotherapy were excluded. Survival curves were plotted using the Kaplan-Meier method. Univariate analysis of factors thought to influence survival was then made using Logrank test. Criteria studied consisted of age, sex, TNM stage, T-status, nodal status, distant metastasis, histological grade, lymphatic and vascular invasion, tumour location, preoperative carcinoembryonic antigen (CEA) level and liver function tests. Multivariate analysis was conducted using Cox regression analysis. RESULTS: The mean survival time for all patients was 42.8 (SEM = 2.8) months. The overall 1-, 3- and 5-year survival rates were 72%, 54% and 47%, respectively. In univariate analysis, patients' age (P < 0.0001), TNM stage (P < 0.0001), T-status (P = 0.015), nodal status (P = 0.016), distant metastasis (P < 0.0001), grade (P = 0.005), lymphatic and vascular invasion (P < 0.0001) and presurgery CEA level > 5 ng/ml (P = 0.021) were found to be predictors that could affect survival. In Cox regression analysis, age (P < 0.0001), TNM stage (P = 0.001) and grade (P = 0.008) were determined as independent prognostic factors of survival. CONCLUSION: Age, TNM stage, T-status, nodal status, distant metastasis, grade, lymphatic and vascular invasion and presurgery CEA level can predict the postsurgical survival rate in patients with colorectal cancer.

Statistical Scoring Procedures Applicable to Laboratory Performance Evaluation.

Two statistical scoring procedures based on p-values have been developed to evaluate the overall performance of analytical laboratories performing environmental measurements. The overall score of bias and standing are used to determine how consistently a laboratory is able to measure the true (unknown) value correctly over time. The overall score of precision and standing are used to determine how well a laboratory is able to reproduce its measurements in the long run. Criteria are established for qualitatively labeling measurements as Acceptable, Warning, and Not Acceptable, and for identifying areas where laboratories should re-evaluate their measurement procedures. These statistical scoring procedures are applied to two real environmental data sets.

A unified approach for assessing agreement for continuous and categorical data.

This paper proposes several Concordance Correlation Coefficient (CCC) indices to measure the agreement among k raters, with each rater having multiple (m) readings from each of the n subjects for continuous and categorical data. In addition, for normal data, this paper also proposes the coverage probability (CP) and total deviation index (TDI). Those indices are used to measure intra, inter and total agreement among all raters. Intra-rater indices are used to measure the agreement among the multiple readings from the same rater. Inter-rater indices are used to measure the agreement among different raters based on the average of multiple readings. Total-rater indices are used to measure the agreement among different raters based on individual readings. In addition to the agreement, the paper also assess intra, inter, and total precision and accuracy. Through a two-way mixed model, all CCC, precision and accuracy, TDI, and CP indices are expressed as functions of variance components, and GEE method is used to obtain the estimates and perform inferences for all the functions of variance components. Each of previous proposed approaches for assessing agreement becomes one of the special case of the proposed approach. For continuous data, when m approaches infinity, the proposed estimates reduce to the agreement indices proposed by Barnhart et al. (2005). When m = 1, the proposed estimate reduces to the ICC proposed by Carrasco and Jover (2003). When m = 1, the proposed estimate also reduces to the OCCC proposed by Lin (1989), King and Chinchilli (2001a) and Barnhart et al. (2002). When m = 1 and k = 2, the proposed estimate reduces to the original CCC proposed by Lin (1989). For categorical data, when k = 2 and m = 1, the proposed estimate and its associated inference reduce to the kappa for binary data and weighted kappa with squared weight for ordinal data.

Clinical and biochemical manifestation produced by scorpion (Hemiscorpius lepturus) venom in experimental animals

Several studies have been published about the clinical and biochemical manifestations produced by the venom of scorpions of the Buthidae family, but very few reports have indicated the manifestations induced by the venom of the Scorpionidae family. Hemiscorpius lepturus is an important scorpion species present in the south and southwestern part of Iran, causing morbidity and mortality in children and adults. For the present study, H. lepturus venom was extracted by electric shock and subcutaneously injected (6.3mg/kg) into a group of six rabbits. Blood collection was carried out before and three hours after venom injection for determination of osmotic fragility and levels of blood sugar, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and alkaline phosphatase (ALP). In vitro studies were also carried out to verify the osmotic fragility of red blood cells (RBCs) exposed to venom concentrations ranging from 0-90µg/2ml blood. Results showed the extreme effect of this venom on the lysis of RBCs both in vitro and in vivo. Venom injection caused significant (p>0.001) increase in ALT, AST, LDH and blood sugar levels. There was also an increase in CPK, and ALP levels after venom injection; however, it was not statistically significant. All animals died four hours after having received the venom. The current study revealed that the neurological effect of H. lepturus venom is similar to that of scorpions of the Buthidae family. However, they differ in RBCs lysis, which was highly significant when induced by H. lepturus venom, probably due to the presence of a type of phospholipase in this venom. Further studies are needed to provide a clearer view of the mechanism of action of H. lepturus venom.(AU)

Seasonal variation of red clover (Trifolium pratense L., Fabaceae) isoflavones and estrogenic activity.

Red clover (Trifolium pratense L., Fabaceae) dietary supplements are currently used to treat menopausal symptoms because of their high content of the mildly estrogenic isoflavones daidzein, genistein, formononetin, and biochanin A. These compounds are estrogenic in vitro and in vivo, but little information exists on the best time to harvest red clover fields to maximize content of the isoflavones and thus make an optimal product. Samples of cultivated red clover above-ground parts and flower heads were collected in parallel over one growing season in northeastern Illinois. Generally, autohydrolytic extracts of above-ground parts contained more isoflavones and had more estrogenic activity in Ishikawa endometrial cells as compared with extracts of flower heads. Daidzein and genistein contents peaked around June to July, while formononetin and biochanin A contents peaked in early September. Flower head and total above-ground parts extracts exhibited differential estrogenic activity in an Ishikawa (endometrial) cell-based alkaline phosphatase induction assay, whereas nondifferential activity was observed for most extracts tested in an MCF-7 (breast) cell proliferation assay when tested at the same final concentrations. Ishikawa assay results could be mapped onto the extracts' content of individual isoflavones, but MCF-7 results did not show such a pattern. These results suggest that significant metabolism of isoflavones may occur in MCF-7 cells but not in Ishikawa cells; therefore, caution is advised in the choice of bioassay used for the biological standardization of botanical dietary supplements.

Optimal designs in stability studies.

New optimality criteria for stability studies are proposed, and the related optimal designs are investigated. For each optimality criterion, optimal designs are identified within a class of competing designs. The property of the optimal designs for detecting slope differences is discussed.

Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense).

Because the prevailing form of hormone replacement therapy is associated with the development of cancer in breast and endometrial tissues, alternatives are needed for the management of menopausal symptoms. Formulations of Trifolium pratense L. (red clover) are being used to alleviate menopause-associated hot flashes but have shown mixed results in clinical trials. The strobiles of Humulus lupulusL. (hops) have been reported to contain the prenylflavanone, 8-prenylnaringenin (8-PN), as the most estrogenic constituent, and this was confirmed using an estrogen receptor ligand screening assay utilizing ultrafiltration mass spectrometry. Extracts of hops and red clover and their individual constituents including 8-PN, 6-prenylnaringenin (6-PN), isoxanthohumol (IX), and xanthohumol (XN) from hops and daidzein, formononetin, biochanin A, and genistein from red clover were compared using a variety of in vitro estrogenic assays. The IC50 values for the estrogen receptor alpha and beta binding assays were 15 and 27 microg/mL, respectively, for hops and 18.0 and 2.0 microg/mL, respectively, for the red clover extract. Both of the extracts, genistein, and 8-PN activated the estrogen response element (ERE) in Ishikawa cells while the extracts, biochanin A, genistein, and 8-PN, significantly induced ERE-luciferase expression in MCF-7 cells. Hop and red clover extracts as well as 8-PN up-regulated progesterone receptor (PR) mRNA in the Ishikawa cell line. In the MCF-7 cell line, PR mRNA was significantly up-regulated by the extracts, biochanin A, genistein, 8-PN, and IX. The two extracts had EC50 values of 1.1 and 1.9 microg/mL, respectively, in the alkaline phosphatase induction assay. On the basis of these data, hops and red clover could be attractive for the development as herbal dietary supplements to alleviate menopause-associated symptoms.

Optimal and efficient crossover designs under different assumptions about the carryover effects.

In certain studies it is desirable or necessary that a subject, such as a patient in a medical trial, receive a treatment in each period. This facilitates a within-subject comparison of the treatments. Designs for studies of this type are called crossover designs or repeated measurements designs. If there are s subjects in p periods, the design should specify which of the t treatments is assigned to subject j in period i, i = 1,... ,p,j = 1,..., s. Equivalently we may think of a design as assigning each subject to one of the t(p) possible treatment sequences. The choice of a design will clearly depend on the values of p, s, and t, to which we will refer as the design parameters. But for any set of design parameters, we will typically still have many design choices. To distinguish between different designs for the same design parameters, we will compare the designs under criteria that are related to the objective of the study. Often the objective is a comparison of the treatments, and we would choose a design that, in some sense, provides good estimates of the treatment differences. For these criteria, a design that is optimal under one statistical model may not be optimal under another. It is therefore also of interest to identify designs that are efficient (relative to an optimal design) for more than one model. The main difference in the models that we will consider is in how the possible first-order carryover effects are modeled. This is a controversial issue, and it is by no means our intent to resolve this here. But a design that is efficient under a variety of plausible models is preferable to one that performs well under one model but poorly under another. Our main focus will be on two models. One of these models has been considered extensively in the literature, while the other is relatively new. For selected design parameters, we will compare selected designs under these models.

Medialization framework surgery for voice improvement after endoscopic cordectomy.

Seven dysphonic patients who had previously undergone total or extended cordectomy underwent laryngeal framework medialization. A minimum 6-month period between cordectomy and framework surgery was enforced to allow the vocal cord to scar and form a fibrous "neocord", to evaluate the voice recovery achieved by speech therapy alone and avoid the risk of operating on a patient with undiagnosed early recurrence. The operation is performed with fiberscopic control under general anesthesia. These operating conditions are required because undermining the fibrous tissue at the inner side of the thyroid ala is a lengthy and laborious procedure. This step is necessary to ensure easy placement of the implant. Caution must be taken to avoid tearing the fibrous tissue, with consequent risk of prosthesis extrusion. The cartilage window is left intact. Whereas cartilage implants remain indicated for minor gaps, we advocate Friedrich's implant for wider gaps. The vocal outcome revealed an increased median maximum phonation time from 5 s (range 2-12 s) to 7.5 s (range 3-23 s); a reduced phonation quotient from 516.5 ml/s (range 235-1000 ml/s) to 222 ml/s (range 146-595 ml/s); a slightly increased modal intensity from 61.5 dB (range 57-75 dB) to 67 dB (range 46-68 dB); an improved intensity range from 24.5 dB (range 16-36 dB) to 30 dB (range 16-62 dB); a steady fundamental frequency from 150 Hz (range 132-290) to 152 Hz (range 125-200); and an increased median spectral analysis class from 2 (range 1-3) to 3 (range 2-4). Subjectively, the patients noted that, throughout the day, phonation required less effort and induced less vocal fatigue.

[Dysphagia and cervical osteophytosis: case report and review of the literature]. / Dysphagie et ostéophyte cervical. Cas clinique et revue de la littérature.

Dysphagia with anterior osteophytosis of the cervical bone is a more and more reported affection, especially after the age of 60. However it remains a rare event. The cause to effect relationship between these two entities should be documented by a complete assessment. Surgical treatment is reserved for patients whose medical treatment has failed. We describe an original case of cervical bone osteophytosis which was diagnosed during an acute and febrile aphagia and review the literature about its assessment and treatment.

Upper airways locations of plasmocytoma.

We report one case of extramedullary plasmocytoma located in the nasopharynx. After 8 years, the tumor recurred in the same location and 3 years later, the patient develop a multiple myeloma. Three clinical and pathological entities of plasmocytoma are described: multiple myeloma, solitary bone plasmocytoma and extramedullary plasmocytoma. When histological examination show plasmocytoma, further examinations can or not reveal a multiple myeloma. In 80% of cases, extramedullary plasmocytoma occur in the upper respiratory tract. This development of multiple myeloma from extramedullary plasmocytoma is seen in 5 to 32% of patients and sometimes an extremely long time is required for the change to occur. The treatments are surgery and radiation in the absence of generalized disease.