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A robust goodness-of-fit test statistic with application to ordinal regression models.

We propose a goodness-of-fit test statistic for linear regression with heterogeneous variance, which is asymptotically chi-square if the given model is correct. The test statistic is computed as a quadratic form of observed minus predicted responses. We apply the method to a linear regression for an ordinal categorical response, the wheezing status of a child (no wheeze, wheeze with cold, wheeze apart from cold) as a function of maternal smoking and city of residence.

Child↗

Radionuclide determination of the relationship between left ventricular contractile state and ejection fraction.

To determine whether the relationship between various measures of left ventricular (LV) contractile state and ejection fraction (EF) is linear in man, we studied 30 patients during right atrial pacing over a range of loading conditions. With the use of micromanometer LV pressures and radionuclide LV volumes, pressure-volume (P-V) loops were generated for each loading condition. Then isochronal, instantaneous P-V data points were obtained by linear regression analysis to attain the maximum slope (Emax) of these time-varying isochrones. Other measures of LV end systole were also used to calculate end-systolic P-V relations in a similar fashion, and indirect P-V relations were obtained from the linear regression analysis of brachial artery peak pressure vs minimum LV volume data points. When the slopes of these LV contractile measures were compared to the radionuclide LV EFs, the linear correlation coefficients ranged from 0.53 to 0.67. After natural log transformation of the LV contractile state and EF data, the correlation coefficients for the polynomial curve fits ranged from 0.80 to 0.88. When the correlation coefficients for the polynomial curve fits of the natural log transformed data were compared to those for the linear regression analyses of the raw data, significant improvements were evident (p less than 0.05). Thus the relationship between various measures of LV contractile state and EF obtained with radionuclide angiography is best approximated by a complex, curvilinear relationship that is due, in part, to the wide range of LV contractile states within the relatively narrow normal range of LV ejection fractions.

Adult↗

Model-independent estimation of lag times with first-order absorption and disposition.

The effectiveness of five model-independent procedures for the estimation of lag times (Tlag) was evaluated. Two new methods utilize early concentrations which are weighted by a term exponential in time. They estimate Tlag by weighted linear regression. One of these approaches evaluates also the time when maximum concentration is reached (Tmax). In addition, three older, empirically used procedures are considered. Two methods apply either the first two or three quantifiable concentrations and estimate the lag time by linear regression. Finally, the last unquantifiable concentration is often used as a measure of lag time. Simulations demonstrated that this procedure had large bias and generally high standard deviation. In contrast, the new methods showed small variation and negligible bias. The procedures applying linear regression had intermediate characteristics. Lag times were evaluated effectively by an average of two observations between Tlag and Tmax.

Biological Availability↗

Auditory biofeedback in spastic diplegia.

Using a simple auditory feedback device that produces a continuous buzzing signal on heel contact, we studied the effects of augmented auditory biofeedback on the gait of four spastic diplegic children. The purpose of the biofeedback was to attempt to increase dorsiflexion at heel strike without causing other compensatory changes at the knee and hip, which might lead to crouch gait. We measured velocity, stride length, and thigh, knee, and ankle angles at the heel strike, midswing, and toe-off phases of gait. Four subjects, aged 5-8 years, were given a standard gait training program, supplemented with biofeedback two times per week in a clinical setting and 1 h daily in a home program over an 8-week period. Three computer video gait analyses of the sagittal plane were conducted without biofeedback in the pre- and posttraining conditions and twice with biofeedback over the course of treatment. We performed linear regression analysis of joint angles at heel strike, midswing, and toe-off as a function of days into the study for each patient. Angle-angle diagrams for a test subject before, during, and after treatment indicate changes toward a normal gait pattern with biofeedback. The linear regression analysis showed a statistically significant (p less than 0.01) shift toward dorsiflexion at heel strike with repeated exposure to biofeedback. A compensatory crouch gait was not induced. The linear regression analyses for hip and knee angles were not statistically significant (p greater than 0.25), indicating a disassociation of movement among hip, knee, and ankle.

Acoustic Stimulation↗

Estimating splenic volume: sonographic measurements correlated with helical CT determination.

OBJECTIVE: The purpose of this study was to determine which sonographic measurements of the spleen most closely correlate with splenic volume as determined on helical CT. MATERIALS AND METHODS: From October 17, 2000, to April 27, 2001, 142 consecutive patients prospectively underwent abdominal helical CT and sonography as part of an evaluation for liver disease. Calculations of splenic volumes were based on 10-mm unenhanced images. Maximum length (ML) and width (W), thickness (T), and craniocaudal length (CCL) were measured sonographically. Standard ellipsoid volume formulas (with the addition of new ellipsoid coefficients) and linear regression formulas were calculated for 117 patients whose examinations were performed within 30 days of each other. Mean percent differences, standard deviations, and 95% confidence intervals (CI) were calculated. RESULTS: We calculated the average difference between sonography- and CT-measured volume and the 95% CI for each of the four initial sonographic volume estimates with the ellipsoid method using two lengths and linear regression using two lengths and compared them to CT-determined volume. The ellipsoid formulas were then adjusted for bias. Linear regression formulas were derived in which splenic volumes were separately calculated on the basis of each of the two lengths. Mean percent differences and standard deviations for ellipsoid formulas with varying coefficients using the three length measurements were also calculated. CONCLUSION: Sonographic measurements allow accurate determination of splenic volume. Estimating splenic volume with the formula 0.524 x W x T x (ML + CCL) / 2 provides the greatest overall accuracy.

Adult↗

Multilevel modeling and practice-based research.

PURPOSE: The health care system in the United States is inherently hierarchical. Patients are "nested" within physicians who in turn are "nested" within practices. Much of the research data gathered in practice-based research networks (PBRNs) also have similar patterns of nesting (clustering). When research data are nested, statistical approaches to the data must account for the multilevel nature of the data or risk errors in interpretation. We illustrate the concept of multilevel structure and provide examples with implications for practice-based research. METHODS: We present a selection of multilevel (hierarchical) models and contrast them with traditional linear regression models, using an example of a simulated observational study to illustrate increasingly complex statistical approaches, as well as to explore the consequences of ignoring clustering in data. Additionally, we discuss other types of outcome data and designs, and the effects of clustering on sample size and power. RESULTS: Multilevel models demonstrate that the effects of physician-level activities may differ from clinic to clinic as well as between rural and urban settings; this variability would be undetected in traditional linear regression approaches. Study conclusions differed when the data were analyzed with multilevel methods compared with traditional linear regression methods. Clustered data also affected sample size; as the intraclass correlation increased and the patients per cluster increased, the required number of patients increased dramatically. CONCLUSIONS: Recognizing and accounting for multilevel structure when analyzing data from PBRN studies can lead to more accurate conclusions, as well as offer opportunities to explore contextual effects and differences across sites. Accommodating multilevel structure in planning research studies can result in more appropriate estimation of required sample size.

Biomedical Research↗

Using smoothing splines for detecting ventilatory thresholds.

A recently developed nonparametric regression technique, called a polynomial smoothing spline, is presented for detecting the ventilatory threshold (VT) and respiratory compensation (RC) points from gas exchange response data taken during an incremental exercise test. This type of curve fitting has the advantage of not requiring investigators to specify, a priori, the form of the underlying model, as is required with all linear regression techniques. This procedure yields a mathematically optimal fitted curve through the O2 uptake (VO2) vs CO2 output (VCO2) data and estimates of the process' first and second derivatives. A breakpoint or threshold is indicated by an increase in the value of the derivative and a peak in the second derivative. To evaluate this approach we analyzed gas exchange data collected on nine healthy subjects during a ramp exercise test (15 W.min-1) to the limits of tolerance. Utilizing this procedure we detected VT and RC breakpoints in four subjects and only VT breakpoints in the remaining five subjects. Our results and those obtained using the more conventional linear regression method were similar for those subjects whose RC points were detected using the smoothing spline procedure. However, using regression techniques for subjects with low or otherwise undetectable RC breakpoints, the linear regression method yielded less reliable results in our hands.

Anaerobic Threshold↗

Three dimensional reconstruction of the left ventricle from four anatomically defined apical two-dimensional echocardiographic views.

A method is described for three dimensional reconstruction of the left ventricle which uses four anatomically defined apical views. It is shown that the algorithms developed for reconstruction and volume estimation provide accurate results when applied to planar views with accurately defined boundaries. The linear regression equation was y = -6.32 + 1.04x, with SEE = +/- 3.4 ml, r = 0.999. For both "in vitro" and "in vivo" studies this method is found to be better than various geometrical models used to estimate volumes from two dimensional tomographic or projection views. The linear regression equation of in vitro fluid volume on volume estimate is y = 8.44 + 0.68x, with SEE = +/- 4.9 ml, r = 0.988. For pooled end diastolic and end systolic volumes (EDV and ESV) determined by three dimensional reconstruction (3-DR) and angiography the linear regression equation is y = 54.50 + 0.50x, with SEE = +/- 33.5 ml, r = 0.670. For stroke volume (SV), the regression equation is y = 21.10 + 0.40x, with SEE = +/- 12.8 ml, r = 0.750, and for ejection fraction (EF) it is y = 1.10 + 0.70x, with SEE = +/- 7.8%, r = 0.840. In patients with ischemic heart disease, the method presented is shown to be better than existing methods of volume estimation. Three dimensional perspective images can be plotted in any orientation as a visual aid to the cardiologist. In vivo studies demonstrate the feasibility of 3-DR, from anatomically defined apical views, in the clinical setting.

Cardiac Volume↗

Growth hormone promotes healing of tibial fractures in the rat.

The effect of administering growth hormone for different periods of time on the mechanical properties of healing rat tibial fractures was investigated after 40 days of healing. Biosynthetic human growth hormone, 2.7 mg/kg body weight/day, was administered to three groups of rats for 1, 2, or 3 weeks following fracture, whereas isotonic saline was administered to a control group for 3 weeks. The ultimate load values and maximum stiffness of the fractures increased in the groups injected with growth hormone for 2 or 3 weeks; linear regression analysis revealed a high probability of a positive linear relationship. In the intact bones an increase in ultimate load, maximum stiffness, and energy absorption at ultimate load was found in the group injected with growth hormone for 3 weeks, with linear regression analysis again showing a high probability of a positive linear relationship.

Animals↗

Neuromechanical characterization of in vivo lumbar spinal manipulation. Part I. Vertebral motion.

OBJECTIVE: To quantify in vivo spinal motions and coupling patterns occurring in human subjects in response to mechanical force, manually assisted, short-lever spinal manipulative thrusts (SMTs) applied to varying vertebral contact points and utilizing various excursion (force) settings. METHODS: Triaxial accelerometers were attached to intraosseous pins rigidly fixed to the L1, L3, or L4 lumbar spinous process of 4 patients (2 male, 2 female) undergoing lumbar decompressive surgery. Lumbar spine acceleration responses were recorded during the application of 14 externally applied posteroanterior (PA) impulsive SMTs (4 force settings and 3 contact points) in each of the 4 subjects. Displacement time responses in the PA, axial (AX), and medial-lateral (ML) axes were obtained, as were intervertebral (L3-4) motion responses in 1 subject. Statistical analysis of the effects of facet joint (FJ) contact point and force magnitude on peak-to-peak displacements was performed. Motion coupling between the 3 coordinate axes of the vertebrae was examined using a least squares linear regression. RESULTS: SMT forces ranged from 30 N (lowest setting) to 150 N (maximum setting). Peak-to-peak ML, PA, and AX vertebral displacements increased significantly with increasing applied force. For thrusts delivered over the FJs, pronounced coupling was observed between all axes (AX-ML, AX-PA, PA-ML) (linear regression, R(2) = 0.35-0.52, P <.001), whereas only the AX and PA axes showed a significant degree of coupling for thrusts delivered to the spinous processes (SPs) (linear regression, R(2) = 0.82, P <.001). The ML and PA motion responses were significantly (P <.05) greater than the AX response for all SMT force settings. PA vertebral displacements decreased significantly (P <.05) when the FJ contact point was caudal to the pin compared with FJ contact cranial to the pin. FJ contact at the level of the pin produced significantly greater ML vertebral displacements in comparison with contact above and below the pin. SMTs over the spinous processes produced significantly (P <.05) greater PA and AX displacements in comparison with ML displacements. The combined ML, PA, and AX peak-to-peak displacements for the 4 force settings and 2 contact points ranged from 0.15 to 0.66 mm, 0.15 to 0.81 mm, and 0.07 to 0.45 mm, respectively. Intervertebral motions were of similar amplitude as the vertebral motions. CONCLUSIONS: In vivo kinematic measurements of the lumbar spine during the application of SMTs over the FJs and SPs corroborate previous spinous process measurements in human subjects. Our findings demonstrate that PA, ML, and AX spinal motions are coupled and dependent on applied force and contact point.

Aged↗

Determination of everolimus in whole blood using the Abbott IMx sirolimus microparticle enzyme immunoassay.

OBJECTIVES: Everolimus (Certican) is a new immunosuppressant derived from sirolimus (Rapamune) with a 2-hydroxyethyl chain at position 40 of the macrolide ring. The aim of our study was to evaluate the possible determination of everolimus in whole blood using a commercialized microparticle enzyme immunoassay for sirolimus determination. DESIGN AND METHODS: Everolimus concentrations were determined in blood samples from 11 kidney transplant patients (n=51) and different control materials (n=35) using the Seradyn Innofluor Certican fluorescence polarization immunoassay (FPIA) and the Abbott IMx sirolimus microparticle enzyme immunoassay (MEIA). RESULTS: The MEIA gave a concentration-dependent cross-reactivity with the everolimus, with a linear regression between the assigned values (y) for the Innofluor Certican calibrators and those obtained (x) using this immunoassay: y=0.96x+0.67 (ma68=0.21 microg/L, r=0.974, p<0.001). The within- and between-run coefficients of variation using the MEIA were <or=7.3%. In analyzing the different blood samples from patients and control materials using the MEIA and FPIA, a linear regression was found: MEIA=0.99FPIA-0.46 (ma68=0.32 microg/L, r=0.967, p<0.001). Correcting the MEIA results by means of the linear regression equation found between the assigned values for the Innofluor Certican calibrators and those obtained using this immunoassay led to a reduction in the deviation with respect to the FPIA values. The possible effect of the hematocrit on the results is analogous for both immunoassays. CONCLUSIONS: The Abbott IMx sirolimus MEIA permits the simple and precise determination of everolimus in whole blood, making it a valid alternative for the therapeutic monitoring of this immunosuppressant agent.

Cross Reactions↗

Characterization of baroreflex gain in the domestic pigeon (Columba livia).

Birds have a remarkable capacity to regulate circulation yet little is known about the avian baroreflex. Although both linear regression and curve-fitting techniques are frequently used to assess baroreflex function in mammals, only the former technique has been used in birds. We characterized baroreflex gain in domestic pigeons (Columba livia) and compared gain values derived from applying linear regression to ramp changes in mean arterial pressure (MAP) to values derived from fitting a four-parameter sigmoidal function to steady-state alterations in MAP. We found that, unlike mammals, pigeons do not display circadian patterns in MAP, HR or gain derived from bolus injections of vasoactive drugs. The pressor, but not depressor response, was attenuated by administration of the NMDA-antagonist ketamine, suggesting that central processing of the baroreflex may be similar in birds and mammals despite anatomical differences in arterial baroreceptive zones. Because graded infusions of vasoactive drugs could not consistently produce a plateau in the HR response, fitting data to a sigmoidal curve was difficult. Thus, we propose that variations of the Oxford method and linear regression analysis are superior method to assess baroreflex gain in pigeons than curve fitting.

Animals↗

Development and validation of a direct, non-destructive quantitative method for medroxyprogesterone acetate in a pharmaceutical suspension using FT-Raman spectroscopy.

A simple linear regression method was developed and statistically validated for the direct and non-destructive quantitative analysis--without sample preparation--of the active pharmaceutical ingredient (API) medroxyprogesterone acetate (MPA) in an aqueous pharmaceutical suspension (150 mg in 1.0 ml) using FT-Raman spectroscopy. The linear regression was modelled by plotting the highest peak intensity of the vector normalized spectral band between 1630 and 1590 cm-1 against different MPA standard suspension concentrations. At this band, no spectral interferences from additives in the suspension are observed. The validated model was used for the quantification of a commercial suspension (150 mg in 1.0 ml) of the commercialized preparations. The same standards and samples were used, respectively, for the development and validation of a simple linear regression model and for the quantitative determination by means of HPLC-with sample preparation-as described for the related substances of MPA in the Ph. Eur. IV. The quantification results obtained by the FT-Raman method corresponded with the claimed label concentration (150.01+/-0.96 mg/ml (n=6)). Applying the HPLC method, however, a systematic error was observed (157.77+/-0.94 mg/ml (n=6)). The direct FT-Raman method hence appears the most reliable for the quantification of the MPA component in suspension, compared to the HPLC method that requires sample preparation. The latter method provides a systematic error because the exact volume or density of a suspension sample is unknown. A precise isolation of fixed volumes from a suspension is rather unfeasible because of the continuous sagging of the suspended particles and their sticking to the used materials in the isolation process.

Chromatography, High Pressure Liquid↗

Growth patterns of human ovarian volume during intrauterine and postnatal organogenesis.

BACKGROUND: Ovarian volumes during pre-pubertal, reproductive or menopausal life in a healthy female have been studied by in vivo and anatomical methods. In contrast, conclusive studies on normal human ovarian volume during intrauterine and postnatal organogenesis, when the folliculogenesis occurs, do not exist. AIM: To assess the growth patterns of ovarian volume during human ovarian definitive histogenesis using morphometric methods. SUBJECTS: Twenty-five left ovaries removed from fetuses, newborns and children with karyotype 46,XX, ranging from 15 to 74 weeks of development. OUTCOME MEASURES: The ovaries were completely cut obtaining serial sections. Ovarian volume was calculated both with the ellipsoid method, using its length, maximum and minimum diameters, and the Cavalieri quantitative morphometric method. The age-related pattern of ovarian volume was studied using linear regression analyses. RESULTS: Ovarian volume calculated with the Cavalieri method increased from 16 mm3 at the 15th week of development to over 300 mm3 at the end of the process, with a 20-fold increase compared to the initial volume. Ovarian volume calculated with the ellipsoid method ranged between 25 to over 380 mm3, with a 15-fold increase. On average, ellipsoidal volume over-estimated the true Cavalieri volume (mean difference -14%, S.D. 29, p=0.014, Student's t-test for paired samples). Linear regression curves were developed to predict ovarian volume at any age. Overall, the approximation was better for Cavalieri volume (approximately, 72% of variance explained by the linear regression) than for ellipsoid volume (59% of explained variance). CONCLUSIONS: During the intrauterine and postnatal organogenesis, the normal growth rate of human ovary was almost linear. The calculation of ovarian volume using Cavalieri method does not depend on assumptions about the organ shape and it appears to be more appropriate.

Female↗

Renovating interval-censored responses.

In this note we provide a general framework for describing interval-censored samples including estimation of the magnitude and rank positions of data that have been interval-censored so as to counteract the effect of censoring. This process of sample adjustment, or renovation, allows samples to be compared graphically, using diagrams (such as boxplots) which are based on ranks. The renovation process is based on Buckley-James regression estimators for linear regression with censored data.

Biometry↗

Leptin in postmenopausal women: influence of hormone therapy, insulin, and fat distribution.

Whether use of hormone-replacement therapy (HRT) influences menopause-related changes in body weight is unclear. HRT may affect energy balance by influencing synthesis of the adipocyte-derived hormone leptin. The objectives of this study were to: 1) identify factors influencing circulating leptin in postmenopausal women; 2) determine whether HRT influences serum leptin after adjusting for confounding factors; and, 3) identify potential independent effects of HRT or leptin on resting energy expenditure (REE). Subjects were 54 postmenopausal women, 45-55 yr old, 35 of whom used HRT (estrogen plus progestin). Total and regional body composition and fat distribution were determined by dual-energy x-ray absorptiometry and computed tomography; fasting serum leptin and insulin, by RIA; and REE, by indirect calorimetry. Stepwise multiple linear regression analysis indicated that serum leptin could best be predicted from total fat mass, fasting serum insulin, and total lean mass [log leptin = 1.08 x log fat mass) + (0.46 x log insulin) + (-1.25 x log lean mass) + 1.88; model R2 = 0.78, P < 0.001]. Multiple linear regression analysis indicated that visceral fat was independently related to leptin (parameter estimate = 0.23, P < 0.05), after adjusting for s.c. abdominal fat and leg fat, as well as lean mass and insulin. After adjusting for total fat mass, total lean mass, and fasting insulin, serum leptin did not differ between users and nonusers of HRT (21.7 +/- 1.0 vs. 20.2 +/- 1.3 ng/mL, P = 0.369, adjusted mean +/- SE, respectively). Serum estradiol was inversely correlated with (adjusted) leptin in non-HRT users (r = -0.50), suggesting that ovarian senescence may lead to an increase in leptin. Multiple linear regression analysis indicated that REE (adjusted for fat mass, fat-free mass, and ethnicity) was not associated with leptin (P = 0.298) or hormone use status (P = 0.999; 1323 +/- 31 vs. 1316 +/- 42 kcal/day, adjusted mean +/- SE for users and nonusers, respectively). These results indicate that, in postmenopausal women: 1) total fat mass, lean mass, and fasting insulin, but not HRT, are significant determinants of serum leptin; 2) visceral and s.c. fat contribute to serum leptin; and, 3) neither HRT nor leptin is independently related to REE.

Absorptiometry, Photon↗

Relationships between uterine and fetal traits in rabbits selected on uterine capacity.

The aim of this study was to investigate whether uterine capacity (UC) in rabbits was related to uterine horn length and weight and whether these uterine traits and vascular supply were related to fetal development and survival. Data from 48 unilaterally ovariectomized (ULO) does of the High and 52 ULO does of the Low UC lines of a divergent selection experiment on UC were used. Does were slaughtered on d 25 of fifth gestation. The High line showed higher ovarian weight (0.08 g, P < 0.05) linked to a higher ovulation rate (1 ovum, P < 0.05) and greater length of the empty uterine horn. There were no differences between lines in the remaining doe traits. The number of implanted embryos and live fetuses, fetal survival, and uterine weight and length were positively associated and explained most of the observed variation. Average weights of the live fetuses and their fetal and maternal placentae were not related to uterine weight and length. The linear regression coefficient of full uterine horn length on the number of live fetuses was 2.43 +/- 0.21. The weight of the full uterine horn showed a small quadratic relationship (P < 0.05) with the number of live fetuses. Full uterine horn length, after adjusting for the number of embryos, was negatively associated (P < 0.001) with the number of dead fetuses. The linear regression coefficient of average fetal placental weight of the live fetuses on number of implanted embryos was higher (P < 0.10) in the Low line (-0.23 +/- 0.04 vs. -0.12 +/- 0.04). The linear regression coefficient of average weight of the live fetuses on the average weight of their fetal placentae was higher (P < 0.10) in the High line (2.56 +/- 0.47 vs. 1.27 +/- 0.57). The High line was more efficient, most likely because an increase in intrauterine crowding has a lesser effect on the development of fetal placentae and fetuses. The fetal position within the uterus did not affect the proportion of dead embryos. Fetuses with placentae receiving a single blood vessel had a higher probability of death (P < 0.001) and the lowest weight. There was no difference between lines for individual weight of the live fetuses, but the High line showed higher individual weights of fetal (P < 0.01) and maternal placentae (P < 0.10). Live fetuses in the midportion of the uterus were lighter in weight (P < 0.05) than in the oviductal and cervical regions (20.3 vs. 21.6 and 21.7g). Increasing uterine capacity increases uterine length and decreases weights of fetus and fetal placenta in rabbits.

Animals↗

A comparison of methods for estimating the kinetic parameters of two simple types of transport process.

Sets of experimental data, with known characteristics and error structures, have been simulated for the Michaelis-Menten equation plus a second term, either for linear transport or for competitive inhibition. The Michaelis-Menten equation plus linear term was fitted by several methods and the accuracy and the precision of the parameter estimates from the several methods were compared. The model-fitting methods were: three for least-squares non-linear regression, computer versions of two graphical methods and of two non-parametric methods. The most precise and accurate method was that of D.W. Marquardt (J. Soc. Ind. Appl. Math. 11 (1963) 431--441). The Michaelis-Menten equation with competitive inhibition was also fitted by several methods, viz., two for least-squared non-linear regression, non-parametric method and four variants of the Preston-Schaeffer-Curran plot (Preston, R.L. et al. (1974) J. Gen. Physiol. 64, 443--467). The most precise and accurate of these was the non-linear regression method of W.W. Cleland (Adv. Enzymol. 29 (1967) 1--32). For both these models, the various graphical methods and non-parametric methods gave poor results and are not recommended.

Binding, Competitive↗