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Techniques for estimating genetic admixture and applications to the problem of the origin of the Icelanders and the Ashkenazi Jews.

A method is introduced for simultaneously using multiple loci to estimate admixture and test goodness of fit of the model of admixture. Deviation of observed frequencies from expectation caused by sources of error such as sampling and/or drift is allowed for all loci in all populations. This allows investigation of the effects of different assumptions about sources of error on the estimates. Admixture is then investigated for Icelanders and Ashkenazi Jews. Results indicate that the Icelanders have a large Norse contribution, and that the Jews may have a small to moderate contribution from the European gene pool. There are some indications that AB0 and G6PD give abnormal estimates of admixture compared to other loci, and that the Jewish gene pool may be derived from additional populations in addition to the populations considered.

ABO Blood-Group System↗

Measurement error in assessing the size of posterior subcapsular cataracts from retroillumination photographs.

Twenty-six eyes with posterior subcapsular opacities of various sizes were photographed with the Neitz-Kawara Retroillumination camera. The outline of the opacity in a single photograph of each opacity was traced onto a transparent plastic overlay twice by two independent outliners. Two methods were used to estimate the area within the outlines of the opacities. In the first, a transparent overlay with a standard grid was used to count the number of boxes within the outlines. The second method used computer planimetry to estimate the area within the tracings. We estimated the measurement error associated with a single outlining of an opacity and the contribution of the measurement error to overall sample size requirements in studies comparing the mean areas of posterior subcapsular opacities. Variability in the measurement techniques contributed fewer than 20 additional subjects to overall sample size estimates, a small contribution to total sample size requirements in most studies. An outliner's inherent variability in outlining an opacity was a much larger contributor to the measurement error than was variability in assessing the area of the outline of the opacity. While within outliner variability was similar for the two persons outlining the opacities, there were systematic differences in the way the two traced the outlines. Variability from the use of separate photographs of the same opacity taken by different photographers was minimal.

Cataract↗

High-resolution alignment of action potential waveforms using cubic spline interpolation.

A cubic spline interpolation technique is applied to the problem of aligning action potential waveforms. Interpolation is an attractive alternative to sampling at many times the Nyquist rate in order to reduce errors caused by asynchronous sampling of rapidly changing waveforms. Alignment is achieved by locating the peak of the interpolated waveform, which can be found by solving a quadratic equation. The waveform is then reconstructed for comparison with existing templates. The technique was tested using simulated noisy, randomly arriving waveforms, the interpolated signal and alignment time errors being computed as functions of the signal/noise ratio. The spline technique is superior in accuracy to sampling at eight-times the Nyquist rate and is comparable to a Fourier-transform-based interpolation algorithm. It is computationally efficient, requiring approximately five multiplications per sample point. The interpolation concept is extended to the principal component technique for separation of action potential waveforms. The energy function is interpolated and used to align the waveforms, after which the interpolated coefficients can be used for high speed classification. The technique shows an improvement in both alignment error and effective signal/noise ratio in comparison with sampling or interpolation to a voltage peak.

Action Potentials↗

Ensemble codes involving hippocampal neurons are at risk during delayed performance tests.

Multielectrode recording techniques were used to record ensemble activity from 10 to 16 simultaneously active CA1 and CA3 neurons in the rat hippocampus during performance of a spatial delayed-nonmatch-to-sample task. Extracted sources of variance were used to assess the nature of two different types of errors that accounted for 30% of total trials. The two types of errors included ensemble "miscodes" of sample phase information and errors associated with delay-dependent corruption or disappearance of sample information at the time of the nonmatch response. Statistical assessment of trial sequences and associated "strength" of hippocampal ensemble codes revealed that miscoded error trials always followed delay-dependent error trials in which encoding was "weak," indicating that the two types of errors were "linked." It was determined that the occurrence of weakly encoded, delay-dependent error trials initiated an ensemble encoding "strategy" that increased the chances of being correct on the next trial and avoided the occurrence of further delay-dependent errors. Unexpectedly, the strategy involved "strongly" encoding response position information from the prior (delay-dependent) error trial and carrying it forward to the sample phase of the next trial. This produced a miscode type error on trials in which the "carried over" information obliterated encoding of the sample phase response on the next trial. Application of this strategy, irrespective of outcome, was sufficient to reorient the animal to the proper between trial sequence of response contingencies (nonmatch-to-sample) and boost performance to 73% correct on subsequent trials. The capacity for ensemble analyses of strength of information encoding combined with statistical assessment of trial sequences therefore provided unique insight into the "dynamic" nature of the role hippocampus plays in delay type memory tasks.

Action Potentials↗

Sample handling for determination of free platinum in blood after cisplatin exposure.

Cisplatin is a commonly used cytostatic drug that can be pharmacokinetically monitored by measurement of non-protein-bound platinum (Pt) in plasma. The present report elucidates some practical aspects on blood sample preparation with the purpose of identifying methodological error sources and simplifying sample handling. Human blood was incubated in vitro with clinically relevant doses of cisplatin and then stored at different temperatures for various periods prior to deproteinization. Pt concentrations were analyzed by inductively coupled plasma mass spectrometry, which is a very sensitive technique that is well suited for determination of free Pt in biological samples. Free Pt concentration is usually determined after ultrafiltration of plasma. An alternative approach used to study the protein-free fraction is to precipitate the proteins with ice-cold ethanol and then analyze the aliquot. We compared the Pt concentrations in protein-free plasma obtained by these two methods and the levels were very similar. Thus, ethanol deproteinization may be an attractive alternative to ultrafiltration, since it is both simple to perform and very cost-effective. Storage of nondeproteinized whole blood or plasma at 4 degrees C or 20 degrees C did not affect the free Pt fraction significantly for the first 2 h, after which a gradual decrease was noted. This suggests that saving the blood sample for approximately 1 h before processing should not have any major impact on the result. On long-term storage of frozen blood samples prior to deproteinization the freezing temperature proved to be of critical importance. At -20 degrees C there was a gradual decrease in the free Pt fraction during the study period of 14 days, whereas the free Pt concentration remained unchanged at -70 degrees C for at least 3 months. Thus, samples may be stored unprocessed at -70 degrees C for several months, whereas -20 degrees C is not sufficiently cold.

Cisplatin↗

Determination of ionized calcium in parotid saliva.

A new method for the determination of ionized calcium in parotid saliva utilizing an automatic ionized calcium analyzer (Orion Biomedical Model Space-Stat 20) was evaluated. The method showed good precision with a relative standard deviation of 2.9--3.8 per cent in the range 0.20--0.79 mmol . l-1 after 226 duplicate measurements. Mean recovery was 94.9% in the range of 0.6--1.8 mmol. l-1. Bovine mucin was found not to interfere with the calcium electrode. Differences in sodium concentration, ionic strength and pH between the standard solutions and samples caused systematic errors. These were corrected using experimentally derived formulas. The influence of pH on the concentration of ionized calcium was studied in 13 parotid saliva samples. A non-linear relationship ranging between 32 and 84% of the total calcium concentration was found.

Animals↗

The significance of treatment effects across several independent studies.

Standardized means can be generated from the t, F or chi 2 statistic used to test the significance of treatment effects in each of several independent studies. An unweighted means ANOVA, calculated from the standardized means, provides tests of significance for the treatment main effect across studies and for the differences in magnitudes of the treatment effects between studies. The protection against Type I errors (false positive conclusions) afforded by the standardized means ANOVA is evaluated in a series of Monte Carlo simulations involving both equal and unequal sample sizes and error variances. A detailed illustration of the method is provided. The combining of information from multiple independent trials in clinical psychopharmacology research is illustrated with regard to problems of establishing the general equivalence of two drugs, as well as in providing a comprehensive conclusion concerning efficacy across several studies that may not appear uniformly positive.

Antipsychotic Agents↗

Deconvolution analysis of hormone data.

Deconvolution analysis of hormone data poses special problems in view of the sparse, noisy, and short data series typically available for analysis; the unknown true nature of the underlying secretory event; and potentially large variations in dissipation or clearance kinetics in different settings. Consequently, deconvolution techniques, which concern themselves with the estimation of hormone secretion and/or clearance based on serial circulating hormone concentration measurements, face a particular challenge. Ideal features of deconvolution algorithms are summarized in Table IV. Specific deconvolution techniques available to analyze hormone data include both waveform-defined procedures and waveform-independent algorithms. These approaches should be viewed as complementary rather than antagonistic. All deconvolution techniques are subject to individual limitations and specific strengths. Independently of the method employed, error propagation is necessary so as to define the statistical uncertainty intrinsic to the estimate of secretion and clearance. Such calculations of experimental uncertainty should include error inherent in the sample collection, processing, and assay as well as error in the kinetic constants and/or anticipated departures of the biological process from the algebraic structure of the convolution formulation. Moreover, more complex convolution statements will be required to describe the full range of behavior of hormone data in a systems view. The applications of such newer convolution methods as well as currently available techniques include model synthesis, model testing, and analysis of the interactions among multiple pulse generators.

Algorithms↗

Measurement of airborne cyanoacrylates.

The behaviour of common alkyl-2-cyanoacrylates in air has been investigated. Increasing humidity was found to increase the rate of polymerisation, although polymerisation is not instantaneous, even at high humidities. Sampling methods for these compounds have been studied and we are able to recommend a pumped Tenax sampling tube, although certain sampling limitations apply, notably that specified flow rates must be applied and that a maximum sampling time of four hours is recommended. Significant errors can occur if sampling is performed outside the range of conditions specified. Upon completion of sampling the tube is desorbed into 0.2% phosphoric acid in acetonitrile. The resulting solution is analysed by HPLC.

Air Pollutants, Occupational↗

Spectrophotometric flow injection determination of trace amounts of thiocyanate based on its reaction with 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol and dichromate: assay of the thiocyanate level in saliva from smokers and non-smokers.

A simple and very sensitive spectrophotometric flow injection (FI) procedure for the determination of trace amounts of thiocyanate is described. The proposed method is based on the reaction between thiocyanate and 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol, which, in 2 mol dm-3 acidic media in the presence of a strong oxidizing agent, produces an intensely coloured product. Several oxidants are potentially applicable, but it is shown that dichromate is preferable. As the reaction product formed is unstable and the signal inherently is recorded on a high background level, it is demonstrated that FI constitutes an ideal method in order to monitor reproducibly and repeatedly the kinetically transient signal that is obtained. Based on optimization by a factorial experimental design, the detection limit of the procedure was found to be 3.5 mumol dm-3, and the standard deviation between samples was 0.16 mumol dm-3. No significant interferences were observed; a 1000-fold excess of cyanide could readily be tolerated within the experimental error. With a sample volume of 50 microliters being injected, the sampling frequency was 60 samples h-1. The system was tested with saliva samples from non-smokers and smokers, and the results show that it is possible to distinguish between these two categories of individuals. As an added benefit, the detection limit of the analytical procedure allows the samples to be diluted 100-fold, so that centrifugation for 5 min is the only preliminary sample preparation that is necessary.

Azo Compounds↗

Qualitative and quantitative assessment of geographic clustering of population samples selected using different methods of random digit dialing.

Random digit dialing is a method commonly used to select random population samples in epidemiologic research. Although random digit dialing is generally presumed to provide representative samples, coverage and nonresponse errors may affect the degree to which the sample is representative. The present investigation was undertaken to determine whether the geographic distributions of samples selected using variations of the basic random digit dialing technique accurately reflect the underlying population distribution, and if not, whether such samples tend to be either more or less dispersed than the populations from which they were selected. Data regarding control groups from three case-control studies conducted from 1983-1986 were utilized. The residence addresses of 998 controls were located and assigned an X-Y coordinate and census tract designation within a three-county geographic area in northwest Washington State. Initially, the spatial distributions of controls were examined graphically in relation to the age-sex structure of the underlying population. No differences in geographic pattern were apparent. A more formal statistical evaluation was conducted based on centrographic techniques utilizing two measures to describe the spatial distribution of a set of points. Results indicate that the samples chosen were neither more nor less dispersed than the underlying populations. However, the geographic centers of samples selected using primary numbers tended to be shifted from the centers of their respective populations. Several possible explanations for such shifts are considered, and extensions of the analytical approach are suggested in relation to the further evaluation of population sampling and the investigation of space-time aggregations of disease.

Adult↗

Measurement of glomerular filtration rate in adults: accuracy of five single-sample plasma clearance methods.

After an intravenous injection of a tracer that is removed from the body solely by filtration in the kidneys, the glomerular filtration rate (GFR) can be determined from its plasma clearance. The method requires a great number of blood samples but collection of urine is not needed. In the present investigation the total plasma clearance of 51Cr-EDTA (ethylenediaminetetra-acetate) was assessed from 13 blood samples taken 5-300 min post-injection in 44 adult patients with GFR greater than 15 ml min-1. In 34 of these patients the plasma clearance of 99Tcm-DTPA (diethylenetriaminepenta-acetate) was determined simultaneously. Using these clearance values as reference the accuracy of six simplified methods were studied: five single-sample methods and one five-sample method. The standard error of estimate (SEE) of the single-sample methods ranged from 4.2 to 7.5 ml min-1 using EDTA, and from 3.8 to 6.3 ml min-1 using DTPA. SEE of the five-samples method was 3.0 ml min-1 (EDTA) and 3.1 ml min-1 (DTPA). The single-sample methods given by Christensen & Groth (1986) and by Tauxe (1986) are recommended for daily use, as SEE was small even at low GFR values. In patients with GFR less than 80 ml min-1, in whom a highly accurate determination is needed, a multiple samples method is recommended, e.g., Brøchner-Mortensen (1972).

Adult↗

Clinical long-term in vivo evaluation of poly(L-lactic acid) porous conduits for peripheral nerve regeneration.

It was the purpose of this study to evaluate the clinical long-term effects of PLLA degradation in vivo on nerve regeneration in the rat sciatic nerve model. Thirty-one Sprague Dawley rats were utilized. Two groups of animals were selected. The control group of 10 animals received a 12 mm reversed isograft into the right sciatic nerve from 5 donor animals. The experimental group (n = 21) received a 12 mm empty PLLA conduits placed into a 12 mm defect in the right sciatic nerve. The left leg served as an internal control. Walking track analysis was performed monthly through 8 months. At the end of 4 and 8 months, animals in the control isograft and experimental group had the medial and lateral gastrocnemius muscles harvested and weighed for comparison. The midconduit/isograft and the distal nerve in these same animals were harvested and histomorphologically analyzed. Multiple samples were collected and expressed as means +/- standard error. A two-sample t-test and Wilcoxon rank sum test was used to compare the variables. Significance level was set at alpha = 0.05. After Bonferroni correction for multiple testing, a p value of < or = 0.01 was considered statistically significant. Throughout all time periods, the PLLA conduit remained structurally intact and demonstrated tissue incorporation and vascularization. There was no evidence of conduit collapse or breakage with limb ambulation. Moreover, there was no evidence of conduit elongation at 8 months as previously observed with the 75:25 poly(DL-lactic-co-glycolic acid) (PLGA) conduits. The mean absolute value of the sciatic functional index (SFI) demonstrated no group differences from isograft controls measured over the 8 months except at 3 months where the isograft values were higher (p = 0.0379) and at 7 months were the isograft group was significantly lower (p = 0.0115). At 4 and 8 months, the weight of the gastrocnemius muscles of the experimental group was not significantly different from isografts. At 4 months the number of axons/mm2 and nerve fiber density was not significantly different between the isograft control and experimental groups in either the midconduit/isograft or distal nerve. At 8 months the number of axons/mm2 was significantly lower in the isograft compared to the midconduit experimental group (p = 0.006). The number of axons/mm2 in the distal nerve and the nerve fiber density in the midconduit and distal nerve were not significantly different between the two groups. The study confirmed our initial hypothesis that PLLA conduits are a viable scaffold for clinical long-term nerve gap replacement. We are critically aware however that longer evaluation of polymer degradation is warrented. Further studies on these individual nerve components are continuing, with the ultimate goal being the fabrication of a bioactive conduit that meets or exceeds the functional results of isografts.

Animals↗

Confidence intervals for the log-normal mean .

In this paper we conduct a stimulation study to evaluate coverage error, interval width and relative bias of four main methods for the construction of confidence intervals of log-normal means: the naive method; Cox's method; a conservative method; and a parametric bootstrap method. The simulation study finds that the naive method is inappropriate, that Cox's method has the smallest coverage error for moderate and large sample sizes, and that the bootstrap method has the smallest coverage error for small sample sizes. In addition, Cox's method produces the smallest interval width among the three appropriate methods. We also apply the four methods to a real data set to contrast the differences.

Bias↗

A statistical approach to the recognition of inferior wall myocardial infarction by the Q/R ratios.

To sharpen ECG criteria for diagnosis of inferior wall myocardial infarction (IWMI), the distribution of Q duration and Q/R ratios in leads 3 and aVF in four groups have been analyzed. Two of these groups are teaching samples (200 ECGs of patients with various diagnoses, but in whom no myocardial infarction was found on post-mortem, and 123 ECGs of patients in whom IWMI was found on post-mortem examinations) and two control samples (408 ECGs of healthy men and 60 ECGs of patients with clinically proved IWMI). The chosen combination of conditions Q/R3 greater than 25 percent and Q/RaVF greater than 10 per cent gives minimal number of errors for the teaching samples. The diagnostic rule gave 5-7 percent errors over the control samples. It is shown that use of Q duration greater than 0.04'' gives less satisfactory results in the diagnosis of IWMI.

Diagnosis, Computer-Assisted↗

Description of analytical problems arising from elevated serum solids.

There has always been a problem with the collection of data and interpretation of the results obtained from any biological fluid in which the solids content was increased to a great extent. Of these solids, the triglycerides of the lipids may cause a plasma (serum) to vary in appearance from opalescent to milky. This condition of the specimen and the concomitant turbidity upon its addition to reagents creates the well-documented optical aberrations of spectrophotometric measurements. In addition, the lipids, in conjunction with the proteins, can act as diluents when they are elevated, thereby decreasing what might be termed the residual true plasma volume. Thus the water content of an aliquot sampled for a particular analytical procedure is diminished, and by that means a situation is created in which a short sample is drawn. This dilution effect by the solids results in a lowering of the assay values obtained for the measured constituents of such a serum sample. An associated phenomenon of high concentrations of solids, especially proteins, is the increase in viscosity of a specimen, a condition that also causes an error of short sampling when certain peristaltic pumping devices are used. This review considers several aspects of problems encountered when dealing with a number of circumstances that are critical to the measurement of analytes in severely hyperlipemic and/or hyperproteinemic specimens. These include the problems of short sampling; the potential amelioration of the problem by corrective mathematics, extraction of the lipids, or ultracentrifugation of the true plasma from the lipids; the important need to include most analytes into our considerations; the difference in reference base values for the calculation of concentrations of lipids of serum versus other analytes; the concept of the use of ratios when the reference base values differ, numerator analyte from denominator analyte; and the problems of using serum blanks when necessary corrective action for the solids volume is neglected. Thus, in the final analysis, problems with underestimated volumes of samples used for many spectrophotometric determinations are considered here along with the other difficulties encountered when the need to measure analytes in serums with extremely high solids content presents.

Blood Chemical Analysis↗

Effects of distraction on children's pain and distress during medical procedures: a meta-analysis.

BACKGROUND: It is difficult to determine the usefulness of distraction to decrease children's distress behavior and pain during medical procedures because many studies use very small samples and report inconsistent findings. OBJECTIVES: To investigate the mean effect sizes across studies for the effects of distraction on young children's distress behavior and self-reported pain during medical procedures. METHOD: Hunter and Schmidt's (1990) procedures were used to analyze 16 studies (total n = 491) on children's distress behavior and 10 studies (total n = 535) on children's pain. RESULTS: For distress behavior, the mean effect size was 0.33 (+/-0.17), with 74% of the variance accounted for by sampling and measurement error. For pain, the mean effect size was 0.62 (+/-0.42) with 35% of the variance accounted for. Analysis of studies on pain that limited the sample to children 7 years of age or younger (total n = 286) increased the amount of explained variance to 60%. CONCLUSIONS: Distraction had a positive effect on children's distress behavior across the populations represented in this study. The effect of distraction on children's self-reported pain is influenced by moderator variables. Controlling for age and type of painful procedure significantly increased the amount of explained variance, but there are other unidentified moderators at work.

Adolescent↗

Improvement in transfusion safety using a specially designed transfusion wristband.

Fatal haemolytic transfusion reaction due to ABO incompatibility occurs mainly as a result of clerical error. A blood sample drawn from the wrong patient and labelled as another patient's will not be detected by the blood bank unless there is a previous ABO grouping result. We report here the detection of such clerical error by the use of a specially designed transfusion wristband. The wristband has the following special features: (i) once attached, it cannot be removed except by cutting; (ii) it has a pocket containing a transfusion label; (iii) a unique transfusion barcode is printed on each transfusion label and the corresponding wristband simultaneously by computer technology; (iv) a transfusion label removed from the wristband after attachment to the patient has a characteristic tear-mark distinguishing it from one removed prior to attachment. The blood bank only accepted those specimens bearing the tear-marked transfusion labels. All blood units for this patient were labelled with this unique transfusion code together with the patient's details. The nurses counter-checked the transfusion code on the blood units against the transfusion code on the patient's transfusion wristband prior to transfusion. If the blood sample for compatibility testing was drawn from the 'wrong' patient, the intended patient either did not carry a wristband or the transfusion codes did not match at all. Pretransfusion compatibility tests were performed on 2189 patient samples using this procedure. It was well accepted by both ward and blood bank staff. Two potential mismatched transfusions were avoided. These two clerical errors would not have been detected because neither patient had previous ABO grouping results.

Blood Banks↗