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PubMed2006

Assessment of femoral neck strength by 3-dimensional X-ray absorptiometry.

Hip fractures due to osteoporosis are accompanied with increased mortality and morbidity. Bone mineral density (BMD [g/cm(2)]) measured by dual-energy X-ray absorptiometry (DXA) is the most important risk factor. However, an overlap exists between results of fractured and nonfractured populations. Macro-architectural parameters of the femur are independent risk factors of fracture. They have been evaluated in two dimensions using X-ray films or DXA scans; therefore, they are highly dependent on patient positioning and interindividual anatomical variations. To overcome this problem, we have previously shown the possibility to reconstruct human femurs using two perpendicular DXA scans and to calculate 3-dimensional (3D) geometric parameters from these reconstructions by a method called 3-dimensional X-ray absorptiometry (3D-XA). The aim of this article is to assess whether the combination of areal BMD and 3D geometric parameters calculated from 3D-XA improves failure load prediction of human proximal femurs in stance phase configuration. Twelve femurs (11 women, 1 man; aged 88+/-9 yr; range: 72-103 yr) were included in this study. The BMD was measured using a Hologic Delphi-W device (Hologic, Waltham, MA) and 3D reconstruction of the femurs was done using two perpendicular DXA scans as previously published. The calculated 3D geometric parameters included femoral neck axis length (FNAL), mid-femoral neck cross-sectional area (mid-FN CSA), neck shaft angle (NSA), and femoral head diameter (FHD). Mechanical testing was performed using stance phase configuration, which resulted in subcapital fractures. The FHD was correlated to mid-FN CSA and FNAL (r=0.68 and 0.76, respectively; p<0.001). Failure load was correlated to age, FHD, NSA, and BMD measurements. Multiple regression analysis showed that femoral neck BMD, FHD, and mid-FN CSA gave the best statistical model for failure load prediction (r(2)=0.84; p<0.002). This is the first study suggesting that combining areal BMD to 3D geometric parameters obtained by 3D-XA improve failure load prediction in human femurs.

Absorptiometry, Photon↗

PubMedDate not supplied

A statistical approach to computer processing of cryo-electron microscope images: virion classification and 3-D reconstruction.

The scattering density of the virus is represented as a truncated weighted sum of orthonormal basis functions in spherical coordinates, where the angular dependence of each basis function has icosahedral symmetry. A statistical model of the image formation process is proposed and the maximum likelihood estimation method computed by an expectation-maximization algorithm is used to estimate the weights in the sum and thereby compute a 3-D reconstruction of the virus particle. If multiple types of virus particle are represented in the boxed images then multiple 3-D reconstructions are computed simultaneously without first requiring that the type of particle shown in each boxed image be determined. Examples of the procedure are described for viruses with known structure: (1). 3-D reconstruction of Flockhouse Virus from experimental images, (2). 3-D reconstruction of the capsid of Nudaurelia Omega Capensis Virus from synthetic images, and (3). 3-D reconstruction of both the capsid and the procapsid of Nudaurelia Omega Capensis Virus from a mixture of unclassified synthetic images.

Algorithms↗

PubMed2004

Nonspecific binding of the OR repressors CI and Cro of bacteriophage lambda.

We estimate the Gibbs free energy for nonspecific binding (DeltaGNSB) to the Escherichia coli DNA for two regulatory proteins of the lambda phage, CI and Cro. By means of a statistical-mechanical approach, we calculate the cI and cro activities associated with the operator OR of an introduced lambda phage genome (prophage). In this statistical model we apply in vitro-measured binding free energies to fit in vivo experimental data for cI and cro activities, respectively, where DeltaGNSB is introduced as a free (fitting) parameter. Without nonspecific binding included in the model, the quality of the description is fairly poor, whereas data are nicely correlating with our model with nonspecific binding included over the entire data range. The obtained values of DeltaGNSB are -4.1+/-0.9 kcal/mol, for CI, and -4.2+/-0.8 kcal/mol, for Cro. In particular, in a lysogen (approximately 250 CI monomers per cell) we conclude that 86% of the total CI in the cell is nonspecifically bound, leaving on average around 10 CI dimers freely available in the E. coli cytoplasma. These findings corroborate the view that due to low free cellular particle numbers a dynamical analysis of genetic regulation at OR and comparable systems should include a stochastic component. In addition, we perform a stability analysis of the OR system in the presence of nonspecific binding.

Bacteriophage lambda↗

PubMed2005

A rapid method for estimation of baculovirus titer based on viable cell size.

Baculovirus protein expression system is a powerful tool for producing recombinant proteins. To optimize conditions for efficient recombinant protein expression, it is important to determine titer of virus stock for arriving at an optimal multiplicity of infection (MOI) that maximizes recombinant protein expression. Traditionally plaque assays have been used for titer determination. Other methods such as endpoint dilution, quantitative real-time polymerase chain reaction and flow cytometry have been developed to aid the determination of virus titers. However, most of these methods are time-consuming and labor intensive. In this regard, a simple and rapid method for determination of virus titers based on the cytopathic effects that lead to viable cell size increase following virus infection is presented in this paper. In this study, the Vi-CELL (Beckman Coulter) was used to measure cell-diameter over a range of virus dilutions, following infection. Applying statistical modeling techniques, the viable cell-diameter data was used to estimate the virus titer. The results indicated that the viable cell-diameter based titer estimation to be reliable and comparable to titers determined by the traditional plaque assay.

Animals↗

PubMed2005

Predicting summer hypoxia in the northern Gulf of Mexico: riverine N, P, and Si loading.

We conducted a statistical analysis to discern the relative strengths of the loading of various forms of nitrogen, phosphorus, dissolved silicate and their molar ratios on the variance in the size of the summertime low oxygen zone found off the Mississippi River, northern Gulf of Mexico. A stable statistical model that included Year and riverine nitrate+nitrite loading for the 2 months prior to the measurement of hypoxic zone size described 82% of its variation in size from 1978 to 2004. The usefulness of the term Year is consistent with the documented increase in carbon stored in sediments after the 1970s, which is when the hypoxic zone is predicted to have become a regular feature on the shelf and to have expanded westward. The increased carbon storage is anticipated to cause a sedimentary respiratory demand influencing the size of the zone, and whose temporal influence is cumulative and transcends the annual variations in nitrogen loading. The variable Year is negatively correlated with the TN:TP ratio in a way that suggests N, not P, has become more important as a factor limiting phytoplankton growth in the last 20 years. Nitrogen, in particular nitrate+nitrite, and not phosphorus, dissolved silicate, or their molar ratios, appears to be the major driving factor influencing the size of the hypoxic zone on this shelf. This conclusion is consistent with cross-system analyses that conclude that the TN:TP ratio in the Mississippi River, currently fluctuating around 20:1, is indicative of nitrogen, not phosphorus, limitation of phytoplankton growth. Nutrient management that places stronger emphasis on reducing nitrogen loading as compared to phosphorus loading, is justified.

Environment↗

PubMed2004

Fast exact leave-one-out cross-validation of sparse least-squares support vector machines.

Leave-one-out cross-validation has been shown to give an almost unbiased estimator of the generalisation properties of statistical models, and therefore provides a sensible criterion for model selection and comparison. In this paper we show that exact leave-one-out cross-validation of sparse Least-Squares Support Vector Machines (LS-SVMs) can be implemented with a computational complexity of only O(ln2) floating point operations, rather than the O(l2n2) operations of a naïve implementation, where l is the number of training patterns and n is the number of basis vectors. As a result, leave-one-out cross-validation becomes a practical proposition for model selection in large scale applications. For clarity the exposition concentrates on sparse least-squares support vector machines in the context of non-linear regression, but is equally applicable in a pattern recognition setting.

Algorithms↗

PubMed2005

Spatial registration of multichannel multi-subject fNIRS data to MNI space without MRI.

The registration of functional brain data to the common brain space offers great advantages for inter-modal data integration and sharing. However, this is difficult to achieve in functional near-infrared spectroscopy (fNIRS) because fNIRS data are primary obtained from the head surface and lack structural information of the measured brain. Therefore, in our previous articles, we presented a method for probabilistic registration of fNIRS data to the standard Montreal Neurological Institute (MNI) template through international 10-20 system without using the subject's magnetic resonance image (MRI). In the current study, we demonstrate our method with a new statistical model to facilitate group studies and provide information on different components of variability. We adopt an analysis similar to the single-factor one-way classification analysis of variance based on random effects model to examine the variability involved in our improvised method of probabilistic registration of fNIRS data. We tested this method by registering head surface data of twelve subjects to seventeen reference MRI data sets and found that the standard deviation in probabilistic registration thus performed for given head surface points is approximately within the range of 4.7 to 7.0 mm. This means that, if the spatial registration error is within an acceptable tolerance limit, it is possible to perform multi-subject fNIRS analysis to make inference at the population level and to provide information on positional variability in the population, even when subjects' MRIs are not available. In essence, the current method enables the multi-subject fNIRS data to be presented in the MNI space with clear description of associated positional variability. Such data presentation on a common platform, will not only strengthen the validity of the population analysis of fNIRS studies, but will also facilitate both intra- and inter-modal data sharing among the neuroimaging community.

Adult↗

PubMed2004

Surveying phylogenetic footprints in large gene clusters: applications to Hox cluster duplications.

Evolutionarily conserved non-coding genomic sequences represent a potentially rich source for the discovery of gene regulatory regions. Since these elements are subject to stabilizing selection they evolve much more slowly than adjacent non-functional DNA. These so-called phylogenetic footprints can be detected by comparison of the sequences surrounding orthologous genes in different species. Therefore the loss of phylogenetic footprints as well as the acquisition of conserved non-coding sequences in some lineages, but not in others, can provide evidence for the evolutionary modification of cis-regulatory elements. We introduce here a statistical model of footprint evolution that allows us to estimate the loss of sequence conservation that can be attributed to gene loss and other structural reasons. This approach to studying the pattern of cis-regulatory element evolution, however, requires the comparison of relatively long sequences from many species. We have therefore developed an efficient software tool for the identification of corresponding footprints in long sequences from multiple species. We apply this novel method to the published sequences of HoxA clusters of shark, human, and the duplicated zebrafish and Takifugu clusters as well as the published HoxB cluster sequences. We find that there is a massive loss of sequence conservation in the intergenic region of the HoxA clusters, consistent with the finding in [Chiu et al., PNAS 99 (2002) 5492]. The loss of conservation after cluster duplication is more extensive than expected from structural reasons. This suggests that binding site turnover and/or adaptive modification may also contribute to the loss of sequence conservation.

Animals↗

PubMed2003

The benefits of improved car secondary safety.

The term 'secondary safety' refers to the protection that a vehicle provides its occupants when involved in an accident. This paper studies information from the British database of road accident reports between 1980 and 1998, to estimate the reduction in the number of occupant casualties over these years which may be attributed to improvements to secondary safety in cars. The paper shows that the proportion of driver casualties who are killed or seriously injured (KSI) is lower for modern cars than for older cars. The reduction of this proportion is used to assess the improvement in secondary safety. Statistical models are developed to represent the proportion with 'year of first registration' as one of the independent variables, although only an incomplete assessment of the benefits of improved secondary safety can be made with the available data. The assessment compares the number of casualties that would have been expected if secondary safety had remained at the level found in cars first registered in 1980 with the actual casualty numbers. It is estimated that improved secondary safety reduced the number of drivers KSI by at least 19.7% in 1998, in comparison with what might have occurred if all cars had had that lower level of secondary safety. This figure relates to all cars on the road in 1998, and rises to 33%, when confined to the most modern cars (those which were first registered in 1998).

Accidents, Traffic↗

PubMed1998

Interpreting the equatorial diffraction pattern of collagenous tissues in the light of molecular motion.

The equatorial diffraction pattern associated with collagenous tissues, particularly type I collagen, is diffuse and clearly unlike that from crystals. Hukins and Woodhead-Galloway proposed a statistical model that they termed a "liquid crystal" for collagen fibers in tendons. Fratzl et al. applied this model to both unmineralized and mineralized turkey leg tendon, a model that ignores the organization imposed by the well-known cross-linking. The justification for adopting this model is that the curve fits the data. It is shown that the data can be equally well matched by fitting a least-squares curve consisting of a second-order polynomial plus a Gaussian. The peak of the Gaussian is taken as the equatorial spacing of the collagen. A physical explanation for this model is given, as is a reason for the changes in the spacing with changes in water content of the tissue. The diffusion is attributed to thermally driven agitation of the molecules, in accordance with the Debye-Waller theory including the Gaussian distribution. The remainder of the diffusion is attributed to other scattering sources like the mineral crystallites.

Animals↗

PubMed1991

Coevolution to the edge of chaos: coupled fitness landscapes, poised states, and coevolutionary avalanches.

We introduce a broadened framework to study aspects of coevolution based on the NK class of statistical models of rugged fitness landscapes. In these models the fitness contribution of each of N genes in a genotype depends epistatically on K other genes. Increasing epistatic interactions increases the rugged multipeaked character of the fitness landscape. Coevolution is thought of, at the lowest level, as a coupling of landscapes such that adaptive moves by one player deform the landscapes of its immediate partners. In these models we are able to tune the ruggedness of landscapes, how richly intercoupled any two landscapes are, and how many other players interact with each player. All these properties profoundly alter the character of the coevolutionary dynamics. In particular, these parameters govern how readily coevolving ecosystems achieve Nash equilibria, how stable to perturbations such equilibria are, and the sustained mean fitness of coevolving partners. In turn, this raises the possibility that an evolutionary metadynamics due to natural selection may sculpt landscapes and their couplings to achieve coevolutionary systems able to coadapt well. The results suggest that sustained fitness is optimized when landscape ruggedness relative to couplings between landscapes is tuned such that Nash equilibria just tenuously form across the ecosystem. In this poised state, coevolutionary avalanches appear to propagate on all length scales in a power law distribution. Such avalanches may be related to the distribution of small and large extinction events in the record.

Biological Evolution↗

PubMed1999

Angiographic quantification of diffuse coronary artery disease: reliability and prognostic value for bypass operations.

OBJECTIVES: Diffuse distal coronary disease is thought to worsen the outcome of coronary bypass operations, but it is not easily quantified. The present study seeks to show that distal coronary diffuseness can be assessed by a structured reading of the coronary angiogram and that the resulting measure predicts operative mortality. METHODS: Sequential survivors (n = 100) and nonsurvivors (n = 34) of nonemergency bypass operations were studied retrospectively. Angiograms were read as follows: (1) Coronary branches at risk were identified; (2) the amount of myocardium supplied by each branch was estimated in steps of 0.5 such that the entire left ventricle added to 8 segments; (3) distal disease severity in each branch was rated on a 5-point scale; and (4) a distal coronary diffuseness score was determined by summing (severity rating x segments supplied) for all branches. Reliability was assessed by correlating the results of blinded re-readings of the same angiograms by the same and different investigators. The score's association with mortality was determined by means of logistic regression. RESULTS: A distal coronary diffuseness score could be determined from all angiograms. Interobserver and intraobserver reliabilities were high, with r values of 0.81 and 0.83, respectively (P <.001). The score was 1 of 3 significant independent predictors of operative mortality, along with nonelective and repeat operations. CONCLUSION: Diffuse distal coronary disease can be quantified by a structured reading of the coronary angiogram and is a powerful independent predictor of surgical death. Inclusion of a standardized measure of this risk factor would improve statistical models of operative risk.

Coronary Angiography↗

PubMed2002

Thresholding rules for recovering a sparse signal from microarray experiments.

We consider array experiments that compare expression levels of a high number of genes in two cell lines with few repetitions and with no subject effect. We develop a statistical model that illustrates under which assumptions thresholding is optimal in the analysis of such microarray data. The results of our model explain the success of the empirical rule of two-fold change. We illustrate a thresholding procedure that is adaptive to the noise level of the experiment, the amount of genes analyzed, and the amount of genes that truly change expression level. This procedure, in a world of perfect knowledge on noise distribution, would allow reconstruction of a sparse signal, minimizing the false discovery rate. Given the amount of information actually available, the thresholding rule described provides a reasonable estimator for the change in expression of any gene in two compared cell lines.

Animals↗

PubMed2003

The relationship of surgeon and hospital volume to outcome after gastric bypass surgery in Pennsylvania: a 3-year summary.

BACKGROUND: This study explores the volume-outcome relationship for gastric bypass surgery for obesity to determine whether higher-volume hospitals, higher-volume surgeons, or both are associated fewer adverse outcomes. METHODS: The Pennsylvania state discharge database was used to identify 4685 cases of gastric bypass surgery for obesity between 1999 and 2001. Statistical modeling analyses were used to determine whether mortality or adverse outcome rate was significantly related to hospital and surgeon volume; the data were controlled for risk factors such as age, gender, comorbidities, and others. RESULTS: There were 28 deaths (0.6%) and 813 adverse outcomes (17.4%). There was a significant risk-adjusted relationship between surgeon volume and adverse outcome, and the same trend was observed for deaths. Surgeons who performed fewer than 10 procedures per year had a 28% risk of adverse outcome and a 5% risk of death, compared with 14% (P<.05) and 0.3% (P=.06), respectively, for high-volume surgeons. Hospital volume did not reach significance, but there was a striking interaction between surgeon and hospital volume; surgeons who performed 10 to 50 cases per year operating in low-volume hospitals had a 55% risk of adverse outcome (P<.01). CONCLUSION: Risk-adjusted in-hospital adverse outcome is significantly lower when gastric bypass is performed by higher-volume surgeons.

Adolescent↗

PubMed2000

The use of an implicit standard for measuring discrimination thresholds.

We measured thresholds for comparing the separation between lines, using either the method of constant stimuli (MCS) or the method of single stimuli (MSS). In the MCS an explicit standard is presented on each trial, whereas in the MSS the standard is the mean of the set. The thresholds for the MSS procedure were nearly identical to those with the MCS procedure, whether or not feedback was used. A statistical model is presented showing how the threshold error estimated by MSS varies according to the number of past stimuli used by the observer to calculate the mean of the set. If the model is an accurate representation of human processing, our observers were averaging over the last 10-20 trials to estimate the implicit standard. Our results show that the explicit standard in the MCS procedure is generally superfluous. Provided that the test range is small, and that the observer is given some practice trials, thresholds measured with MSS procedure are just as precise as those measured with the traditional MCS procedure.

Differential Threshold↗

PubMed2002

Recent declines in mercury concentration in a freshwater fishery: isolating the effects of de-acidification and decreased atmospheric mercury deposition in Little Rock Lake.

The atmospheric deposition of H+, SO4, and Hg to Little Rock Lake in northern Wisconsin has declined substantially during the past decade. Parallel decreases have been observed in the surface waters of the lake. Here we extend the observations to the fish community and we present evidence of a contemporaneous decline in levels of Hg in fish tissue. By comparing data from two separated basins of the lake, we then make an initial effort to isolate and quantify the relative importance of de-acidification and reduced Hg deposition on mercury contamination in fish. Statistical modeling indicates that fish Hg in both basins decreased by roughly 30% between 1994 and 2000 (-5%/y) due to decreased atmospheric Hg loading. De-acidification could account for an additional 5% decrease in one basin (-0.8%/y) and a further 30% decrease in the other basin (-5%/y), since the basins de-acidified at very different rates. These results are consistent with the hypothesis that depositional inputs of SO4 and Hg(II) co-mediate the biosynthesis of methyl mercury and thereby co-limit bioaccumulation. And they suggest that modest changes in acid rain or mercury deposition can significantly affect mercury bioaccumulation over short-time scales.

Acid Rain↗

PubMed1998

Development of fish mercury concentrations in Finnish reservoirs from 1979 to 1994.

Mercury (Hg) concentrations in burbot (Lota lota), perch (Perca fluviatilis), northern pike (Esox lucius), roach (Rutilus rutilus), whitefish (Coregonus lavaretus) and peled (C. peled) were monitored in 18 reservoirs situated in western and northern Finland over a period of 16 years (1979-1994). The reservoirs were impounded from 1964 to 1980. The surface areas ranged between 1 and 417 km2. Data from downstream sites and reference lakes were compared to reservoir mercury data. Generally, fish Hg concentrations in reservoirs exceeded those in natural lakes. Shortly after inundation, fish mercury concentrations clearly increased and remain 15-25 years above background concentrations. The mean Hg concentrations in standardized 1 kg pike from 1989 to 1993 was 0.45 mg/kg in natural lakes and 0.58 mg/kg in reservoirs. The 1 mg/kg fish Hg level recommended by health authorities as the upper limit for human consumption was still exceeded in two reservoirs 20 years old or more. The two largest reservoirs (24 and 27 years old in 1994) with significant commercial fishing had Hg levels below 0.5 mg/kg in all fish species studied. Statistical models for predicting the Hg concentrations in the weight standardized pike were verified with the observed data. For most of the reservoirs, predictions from models based on pH, organic matter (COD) in water, the extent of water level regulation and reservoir age agreed well with observed data. In the most southern, new (under 20 years old) and heavily regulated reservoirs, pike Hg concentration followed a logarithmic function of reservoir age. Model predictions of mercury in pike in the planned Vuotos reservoir (in northern Finland) predicted that Hg would exceed 1 mg/kg Hg for the first 12 years after the flooding.

Animals↗

PubMed1998

Bioaccumulation of mercury in pelagic freshwater food webs.

Current paradigms regarding the bioaccumulation of mercury are rooted in observations that monomethyl mercury (meHg) biomagnifies along pelagic food chains. However, mechanisms regulating the formation of meHg, its initial incorporation at the base of pelagic food chains, and its subsequent trophic transfer remain controversial. Here we use field data from 15 northern Wisconsin lakes, equilibrium aqueous speciation modeling, and statistical modeling to revisit several hypotheses about the uptake, distribution, and fate of inorganic Hg (HgII) and meHg in aquatic biota. Our field data comprise determinations of total Hg (HgT) and meHg in surface waters, sediments, microseston, zooplankton, and small fish in each of the study lakes. For these lake waters, strong positive correlations between DOC and aqueous concentrations of mercury along with negative correlations between DOC and the seston-water partitioning of mercury indicate that organic ligands bind HgII and meHg strongly enough to dominate their apparent aqueous speciation. In the microseston, zooplankton and fish, meHg concentrations and bioaccumulation factors (BAFs) increased with increasing trophic level while biotic concentrations of HgII decreased--indicating that meHg was indeed the biomagnified species of mercury. For all trophic levels, meHg concentrations varied positively with the calculated aqueous concentration of meHg+ (free ion), especially when coupled with pH, or meHgOH (hydroxide) species but not with meHgCl0, the neutral chloride complex. These findings suggest that: (1) the passive uptake of meHg does not control bioaccumulation at the base of aquatic food webs in nature (i.e. phyto- and bacterioplankton); (2) correlation with pH and DOC largely reflect the supply and bioavailability of meHg to lower trophic levels; and (3) meHg concentrations at higher trophic levels reflect uptake at low trophic levels and other factors, such as diet and growth. Low concentrations of meHg in surficial sediments indicate that the fates of biotic HgII and meHg are different. Most biotic meHg is demethylated rather than buried in lake sediments.

Animals↗