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PubMed2006

Regional correlation of structure and function in glaucoma, using the Disc Damage Likelihood Scale, Heidelberg Retina Tomograph, and visual fields.

PURPOSE: To evaluate relationships between the Disc Damage Likelihood Scale (DDLS), global and sectoral structural parameters provided by the Heidelberg Retina Tomograph (HRT), and global and regional functional loss in visual field (VF) testing. DESIGN: Consecutive observational case series. PARTICIPANTS: One hundred ten eyes from 110 patients categorized as glaucoma, glaucoma suspect, or normal. METHODS: Participants were examined clinically to grade the DDLS score and were tested with HRT and Swedish Interactive Threshold Algorithm standard 24-2 VF tests. All tests were performed within 6 months of each other by examiners masked to the other findings. For each patient, the eye with the worse mean deviation (MD) of the VF test was enrolled in the study. Each field was divided into 6 sectors based on a published scheme, and the MD for each sector was calculated. The relationships among clinical DDLS score, HRT parameters, and VF indexes were analyzed by correlation coefficients and linear regression analysis. MAIN OUTCOME MEASURES: The relationship between the DDLS score, global and sectoral optic disc (HRT) parameters, and global and sectoral VF MDs was evaluated. RESULTS: The DDLS showed significant correlation with all global and sectoral VF indexes (r = -0.39 to -0.62, all Ps < 0.0001) and with sectoral rim area HRT measurements (r = -0.27 to -0.51, all Ps < 0.006). The DDLS correlated most strongly with superior and inferior regional data from HRT and VF, and less well with temporal and nasal data. Heidelberg Retina Tomograph rim area and rim volume were the only HRT parameters to correlate moderately with global VF MD (r = 0.30, P = 0.0018, and r = 0.28, P = 0.0030, respectively). Sectoral HRT rim area correlated moderately strongly with the corresponding sectoral VF MDs in the superior and inferior sectors (r = 0.35-0.46, P = <0.0001-0.04). CONCLUSION: Clinical disc assessment and laser tomographic data that determine the state of the neuroretinal rim are associated with sensitivity loss in VF testing in corresponding regions.

Adolescent↗

PubMed2006

Iterative reconstruction techniques in emission computed tomography.

In emission tomography statistically based iterative methods can improve image quality relative to analytic image reconstruction through more accurate physical and statistical modelling of high-energy photon production and detection processes. Continued exponential improvements in computing power, coupled with the development of fast algorithms, have made routine use of iterative techniques practical, resulting in their increasing popularity in both clinical and research environments. Here we review recent progress in developing statistically based iterative techniques for emission computed tomography. We describe the different formulations of the emission image reconstruction problem and their properties. We then describe the numerical algorithms that are used for optimizing these functions and illustrate their behaviour using small scale simulations.

Algorithms↗

PubMed2003

Dntf-2r, a young Drosophila retroposed gene with specific male expression under positive Darwinian selection.

A direct approach to investigating new gene origination is to examine recently evolved genes. We report a new gene in the Drosophila melanogaster subgroup, Drosophila nuclear transport factor-2-related (Dntf-2r). Its sequence features and phylogenetic distribution indicate that Dntf-2r is a retroposed functional gene and originated in the common ancestor of D. melanogaster, D. simulans, D. sechellia, and D. mauritiana, within the past 3-12 million years (MY). Dntf-2r evolved more rapidly than the parental gene, under positive Darwinian selection as revealed by the McDonald-Kreitman test and other evolutionary analyses. Comparative expression analysis shows that Dntf-2r is male specific whereas the parental gene, Dntf-2, is widely expressed in D. melanogaster. In agreement with its new expression pattern, the Dntf-2r putative promoter sequence is similar to the late testis promoter of beta2-tubulin. We discuss the possibility that the action of positive selection in Dntf-2r is related to its putative male-specific functions.

Animals↗

PubMed2005

Biodemographic analysis of male honey bee mortality.

Biodemographic studies of insects have significantly enhanced our understanding of the biology of aging. Eusocial insects have evolved to form different groups of colony members that are specialized for particular tasks and highly dependent on each other. These different groups (castes and sexes) also differ strongly in their life expectancy but relatively little is known about their mortality dynamics. In this study we present data on the age-specific flight activity and mortality of male honey bees from two different genetic lines that are exclusively dedicated to reproduction. We show that males initiating flight at a young age experience more flight events during their lifetime. No (negative) relation between the age at flight initiation and lifespan exists, as might be predicted on the basis of the antagonistic pleiotropy theory of aging. Furthermore, we fit our data to different aging models and conclude that overall a slight deceleration of the age-dependent mortality increase at advanced ages occurs. However, mortality risk increases according to the Gompertz-Makeham model when only days with flight activity (active days) are taken into account. Our interpretation of the latter is that two mortality components act on honey bee males during flight: increasing, age-dependent deaths (possibly from wear-and-tear), and age-independent deaths (possibly due to predation). The overall mortality curve is caused by the interaction of the distribution of age at foraging initiation and the mortality function during the active (flight) lifespan.

Aging↗

PubMed1997

Modelling repeated-series longitudinal data.

We present a model for describing repeated-series longitudinal data, that is, longitudinal data where each unit may yield multiple series of the same variable. Such data arise commonly in ophthalmologic studies, where one obtains measurements on the same variable for the right and left eyes at each clinic visit. We model the mean as a linear function of predictors, and assume that the error term is a sum of a random subject effect and a vector AR(1) process. We fit the model by maximum likelihood and assess the adequacy of the error assumptions by an extension of the empirical semivariogram. We apply our model for data from a clinical trial comparing two treatments for ocular hypertension and glaucoma, with intra-ocular pressure as the primary endpoint. Results suggest that autocorrelation within and between eyes is a significant feature of the variance model. Standard errors depend critically on the variance assumption.

Algorithms↗

PubMed1999

Accounting for evolutionary rate variation among sequence sites consistently changes universal phylogenies deduced from rRNA and protein-coding genes.

Phylogenetic analyses of gene and protein sequences have led to two major competing views of the universal phylogeny, the evolutionary tree relating the three kinds of living organisms, Bacteria, Archaea, and Eukarya. In the first scheme, called "the archaebacterial tree, " organisms of the same type are clustered together. In the second scenario, called "the eocyte tree," the archaeal phylum of Crenarchaeota is more closely related to eukaryotes than are other Archaea. A major property of the evolution of functional ribosomal and protein-encoding genes is that the rate of nucleotide and amino acid substitution varies across sequence sites. Here, using distance-based and maximum-likelihood methods, we show that universal phylogenies of ribosomal RNAs and RNA polymerases built by ignoring this variation are biased toward the archaebacterial tree because of attraction between long branches. In contrast, taking among-site rate variability into account gives support for the eocyte tree.

Animals↗

PubMed1998

Stress-induced reversible and mild-to-moderate irreversible thallium defects: are they equally accurate for predicting recovery of regional left ventricular function after revascularization?

BACKGROUND: In patients with coronary artery disease, stress-redistribution-reinjection thallium scintigraphy provides important information regarding myocardial ischemia and viability. Although both reversible and mild-to-moderate irreversible thallium defects retain metabolically active, viable myocardium, we hypothesized that stress-induced reversible thallium defects may better differentiate reversible from irreversible regional left ventricular dysfunction after revascularization. METHODS AND RESULTS: Twenty-four patients with chronic coronary artery disease underwent prerevascularization and postrevascularization exercise-redistribution-reinjection thallium single photon emission CT, gated MRI, and radionuclide angiography. After revascularization, mean left ventricular ejection fraction increased from 30+/-9% to 37+/-13% at rest (P<0.001). Before revascularization, abnormal contraction at rest was observed in 56 of 110 reversible and 20 of 37 mild-to-moderate irreversible thallium defects (51% and 54%, respectively). After revascularization, regional contraction improved in 44 of 56 reversible compared with 6 of 20 mild-to-moderate irreversible thallium defects (79% and 30%, respectively; P<0.001). The final thallium content (maximum tracer uptake on redistribution-reinjection images) was significantly higher in regions with reversible defects that improved than in those that did not improve after revascularization (86+/-16% versus 66+/-9%, P<0.001). In contrast, final thallium content was similar in regions with mild-to-moderate irreversible defects that improved and in those that did not improve after revascularization (69+/-9% versus 65+/-10%, P=NS). Furthermore, when asynergic regions were grouped according to the final thallium content, at 60% threshold value, functional recovery was observed in 83% of regions with reversible defects compared with 33% of regions with mild-to-moderate irreversible defects (P<0.001). CONCLUSIONS: These findings suggest that although both reversible and mild-to-moderate irreversible thallium defects after stress retain viable myocardium, the identification of reversible thallium defect on stress in an asynergic region more accurately predicts recovery of function after revascularization. Even at a similar mass of viable myocardial tissue (as reflected by the final thallium content), the presence of inducible ischemia is associated with an increased likelihood of functional recovery.

Adult↗

PubMed2002

Positive darwinian selection promotes heterogeneity among members of the antifreeze protein multigene family.

A variety of organisms have independently evolved proteins exhibiting antifreeze activity that allows survival at subfreezing temperatures. The antifreeze proteins (AFPs) bind ice nuclei and depress the freezing point by a noncolligative absorption-inhibition mechanism. Many organisms have a heterogeneous suite of AFPs with variation in primary sequence between paralogous loci. Here, we demonstrate that the diversification of the AFP paralogues is promoted by positive Darwinian selection in two independently evolved AFPs from fish and beetle. First, we demonstrate an elevated rate of nonsynonymous substitutions compared to synonymous substitutions in the mature protein coding region. Second, we perform phylogeny-based tests of selection to demonstrate a subset of codons is subjected to positive selection. When mapped onto the three-dimensional structure of the fish antifreeze type III antifreeze structure, these codons correspond to amino acid positions that surround but do not interrupt the putative ice-binding surface. The selective agent may be related to efficient binding to diverse ice surfaces or some other aspect of AFP function.

Amino Acid Sequence↗

PubMed2003

Pattern ERG correlates of abnormal fundus autofluorescence in patients with retinitis pigmentosa and normal visual acuity.

PURPOSE: To examine the functional significance of central abnormalities present in fundus autofluorescence (AF) images in patients with rod-cone dystrophy and good visual acuity. METHODS: Thirty patients were selected according to three criteria: a clinical diagnosis of retinitis pigmentosa (RP) confirmed with International Society for Clinical Electrophysiology of Vision (ISCEV) standard ERGs, a parafoveal ring of increased high density on fundus AF imaging, and a visual acuity of 20/30 or better. Macular function was assessed with pattern electroretinography (PERG) to checkerboard stimuli of different field sizes. Fundus AF imaging was performed with a confocal scanning laser ophthalmoscope. RESULTS: The radius of the parafoveal ring of high density varied between 1.5 degrees and 9 degrees. The PERG P50 amplitude correlated highly with the radius of the ring of increased autofluorescence (r = 0.80, P < 0.0005, n = 30). PERGs to smaller circular field sizes were present, but increasing field size to beyond that of the high-density autofluorescence ring did not produce further increases in P50 amplitude. There was a high correlation between the minimum stimulus size required to elicit a maximum-amplitude PERG and the radius of the ring (r = 0.87). CONCLUSIONS: The high correlation between AF imaging and PERG, an established technique in the assessment of central retinal function, demonstrates the likelihood that autofluorescence abnormalities have functional significance and may therefore be a valuable additional parameter in the monitoring of these patients.

Adolescent↗

PubMed1995

Using the standard staircase to measure the point of subjective equality: a guide based on computer simulations.

In experiments that measure a point of subjective equality, it is necessary to employ a psychophysical technique that measures the 50% point (P50) on the psychometric function. The standard staircase is an attractive candidate, because its simplicity makes it easy to understand and implement. However, Pentland (1980, Perception & Psychophysics, 28, 377-379) found his own maximum likelihood method (Best PEST) to be considerably less variable than the standard staircase. Here, computer simulations were used to study the effects of manipulating several parameters of the standard staircase in order to try to find a variant that would be competitive with the performance of Best PEST. A graphical summary of some of the standard staircase implementations that were found to be most stable is presented in order that investigators may choose easily the parameters best suited to their requirements. A comparison with an implementation of Pentland's Best PEST failed to replicate Pentland's finding, suggesting that investigators should have no misgivings about the standard staircase in experiments that measure a point of subjective equality.

Algorithms↗

PubMed2002

Information-theoretic analysis of protein sequences shows that amino acids self-cluster.

We analyse for each of 20 amino acids X the statistics of spacings between consecutive occurrences of X within the well-characterized Saccharomyces cerevisiae genome. The occurrences of amino acids may exhibit near random, clustered or smoothed out behaviour, like one-dimensional stochastic processes along the protein chain. If amino acids are distributed randomly within a sequence, then they follow a Poisson process, and a histogram of the number of observations of each gap size would asymptotically follow a negative exponential distribution. The novelty of the present approach lies in the use of differential geometric methods to quantify information on sequencing of amino acids and groups of amino acids, via the sequences of intervals between their occurrences. The differential geometry arises from an information-theoretic distance function on the two-dimensional space of stochastic processes subordinate to gamma distributions-which latter include the random process as a special case. We find that maximum-likelihood estimates of parametric statistics show that all 20 amino acids tend to cluster, some substantially. In other words, the frequencies of short gap lengths tend to be higher and the variance of the gap lengths is greater than expected by chance. This may be because localizing amino acids with the same properties may favour secondary structure formation or transmembrane domains. Gap sizes of 1 or 2 are generally disfavoured, 1 strongly so. The only exceptions to this are Gln and Ser, as a result of poly(Gln) or poly(Ser) sequences. There are preferences for gaps of 4 and 7 that can be attributed to alpha -helices. In particular, a favoured gap of 7 for Leu is found in coiled coils. Our method contributes to the characterization of whole sequences by extracting and quantifying stable stochastic features.

Amino Acids↗

PubMed1998

Modelling time-dependent interaction in a time-varying covariate and its application to rejection episodes and kidney transplant failure.

Acute rejection episodes are thought to be prognostic of eventual kidney graft failure. The influence of rejection events on the hazard of transplant failure appears to be a complex function of how long after transplantation the rejection event occurs as well as the time elapsed since the rejection event. To examine the nature of this relationship, we propose a penalized likelihood approach to estimate the parameters of a two-dimensional rectanglewise constant hazard model. The approach appears to be fairly successful at modelling time dependency in a time-varying covariate. The approach is equally applicable for modelling fixed covariates that act in a jointly nonproportional (non-log-linear) and time-dependent manner.

Analysis of Variance↗

PubMed2004

An experimental method for measuring the mean length of cerebellar parallel fibers: validation and derivation of a correction factor by computational simulation and probability analysis.

The length of cerebellar parallel fibers is important for information integration by the Purkinje cells. Based on the Copernican principle for analyzing the length of stochastic events, we have recently devised a stochastic method to estimate the mean length of parallel fibers within a given cerebellar region. The purpose of the present report is to provide validation of this methodology via computational simulations. We create virtual parallel fibers with known lengths and program each step of our stochastic method for computational simulation. We then compare the observed mean length obtained from our computational simulation with the known mean length of the virtual parallel fibers. In particular, we investigate the effect of cutting parallel fibers into segments during histological sectioning. Our computational results reveal an over-estimation factor ranging from 1.0 (no correction is necessary) to 2.0 as the parallel fiber segmentation becomes increasingly severe. Based on probability theory considerations, we have confirmed the existence of this over-estimation. We have further determined the cause of this over-estimation to be an artificial consequence of one of the sampling steps in our stochastic method. These results provide validation of our methodology, as well as a correction factor, which can be derived directly from the experimentally measured parameters and used to obtain the true mean length of parallel fibers. Potential applications of the stochastic method include a comparative analysis of the length of parallel fibers as an approach to gain clues about cerebellar circuit principles and function. In addition, the stochastic method may also find promising applications in other functionally important axonal systems in the brain.

Cerebellar Cortex↗

PubMed2006

Estrogen receptor-related receptors in the killifish Fundulus heteroclitus: diversity, expression, and estrogen responsiveness.

The estrogen receptor-related receptors (ERRs) are a group of nuclear receptors that were originally identified on the basis of sequence similarity to the estrogen receptors. The three mammalian ERR genes have been implicated in diverse physiological processes ranging from placental development to maintenance of bone density, but the diversity, function, and regulation of ERRs in non-mammalian species are not well understood. In this study, we report the cloning of four ERR cDNAs from the Atlantic killifish, Fundulus heteroclitus, along with adult tissue expression and estrogen responsiveness. Phylogenetic analysis indicates that F. heteroclitus (Fh)ERRalpha is an ortholog of the single ERRalpha identified in mammals, pufferfish, and zebrafish. FhERRbetaa and FhERRbetab are co-orthologs of the mammalian ERRbeta. Phylogenetic placement of the fourth killifish ERR gene, tentatively identified as FhERRgammab, is less clear. The four ERRs showed distinct, partially overlapping mRNA expression patterns in adult tissues. FhERRalpha was broadly expressed. FhERRbetaa was expressed at apparently low levels in eye, brain, and ovary. FhERRbetab was expressed more broadly in liver, gonad, eye, brain, and kidney. FhERRgammab was expressed in multiple tissues including gill, heart, kidney, and eye. Distinct expression patterns of FhERRbetaa and FhERRbetab are consistent with subfunctionalization of the ERRbeta paralogs. Induction of ERRalpha mRNA by exogenous estrogen exposure has been reported in some mammalian tissues. In adult male killifish, ERR expression did not significantly change following estradiol injection, but showed a trend toward a slight induction (three- to five-fold) of ERRalpha expression in heart. In a second, more targeted experiment, expression of ERRalpha in adult female killifish was downregulated 2.5-fold in the heart following estradiol injection. In summary, our results indicate that killifish contain additional ERR genes relative to mammals, including ERRbeta paralogs. In addition, regulation of ERRalpha expression in killifish apparently differs from regulation in mammals. Together, these features may facilitate determination of both conserved and specialized ERR gene functions.

Amino Acid Sequence↗

PubMed2004

Conditional mixed models adjusting for non-ignorable drop-out with administrative censoring in longitudinal studies.

In this paper, a class of conditional mixed models is proposed to adjust for non-ignorable drop-out, while also accommodating unequal follow-up due to staggered entry and administrative censoring in longitudinal studies. Conditional linear and quadratic models which model subject-specific slopes as linear or quadratic functions of the time-to-drop-out, as well as pattern mixture models are both special cases of this approach. We illustrate these models and compare them with the usual maximum likelihood approach assuming ignorable drop-out using data from a multi-centre randomized clinical trial of renal disease. Simulations under various scenarios where the drop-out mechanism is ignorable and non-ignorable are employed to evaluate the performance of these models.

Blood Pressure↗

PubMed2003

Nonstress delayed-enhancement magnetic resonance imaging of the myocardium predicts improvement of function after revascularization for chronic ischemic heart disease with left ventricular dysfunction.

BACKGROUND: The extent of myocardial scarring of the left ventricle (LV) is important in patients with chronic ischemic heart disease (CIHD). With delayed-enhancement magnetic resonance imaging (DE-MRI), scarred myocardium (hyper-enhanced) is easily distinguishable from viable (dark) myocardium. This investigation assessed the use of DE-MRI for predicting functional improvement after coronary artery bypass grafting (CABG) in patients with CIHD and significant LV dysfunction. METHODS: The patient population (n = 29) with CIHD and LV dysfunction (ejection fraction 28% +/- 10%) underwent both DE-MRI, to delineate scarred regions before revascularization, and echocardiography (Echo), to assess segmental function before and after CABG (interval 188 +/- 57 days). Using a 16-segment model, LV myocardium was semiquantitatively analyzed for scarring based on DE-MRI and for improvements in resting function by pre- and post-CABG Echo. RESULTS: Before CABG, 82% of targeted myocardial segments had abnormal contraction; 78% showed scarring, including 38% with greater than mild amounts (25%-100%). Normal contraction was found in 18% of segments before revascularization; scarred areas were identified in 42%, 84% of which had, at most, minimal amounts (0%-24%). Of segments with pre-CABG dysfunction, 82% with no evidence of scar recovered, compared to only 18% with > or =50% scarring. Amount of hyper-enhancement was a very good indicator of improvement of function, especially at the > or =50%/segment threshold; overall accuracy was 0.74 (95% CI 0.66-0.82, P <.001). CONCLUSIONS: In patients with CIHD and significant LV dysfunction, DE-MRI can predict likelihood of functional improvement after revascularization.

Adult↗

PubMed2005

Applications of ancestral protein reconstruction in understanding protein function: GFP-like proteins.

Recreating ancestral proteins in the laboratory increasingly is being used to study the evolutionary history of protein function. More efficient gene synthesis techniques and the decreasing costs of commercial oligosynthesis are making this approach both simpler and less expensive to perform. Developments in ancestral reconstruction methods, particularly more realistic likelihood models of molecular evolution, allow for the accurate reconstruction of more ancient proteins than previously possible. This chapter reviews phylogenetic methods of ancestral inference, strategies for investigating alternative reconstructions, gene synthesis, and design, and an application of these methods to the reconstruction of an ancestor in the green fluorescent protein family.

Amino Acid Sequence↗

PubMed1997

A sequential design for psychophysical experiments: an application to estimating timing of sensory events.

An experimental subject sequentially receives different levels of a stimulus, and data are recorded on response or non-response to the stimulus. To ensure that the subject cannot predict the next stimulus level based on previous stimulus levels, a randomized design, based on a generalized Pólya urn model, is used to allocate the stimulus levels. The goal of the experiment is to elicit information efficiently about the relationship between stimulus level and response (either for an individual subject or a group of independent subjects), by estimating quantiles of the stimulus-response curve. Our design allocates stimulus levels unimodally and symmetrically around the unknown median of the stimulus-response curve. We discuss estimation under a broad family of distributions and also fully discuss design issues and options. This design was used for an experiment in neurophysiology in humans to estimate the timing of onset of kinesthetic stimuli. Such psychophysical studies can increase our understanding of normal and pathological function. We present data from that experiment.

Adult↗