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PubMed2002

Evolution of the sulfide-binding function within the globin multigenic family of the deep-sea hydrothermal vent tubeworm Riftia pachyptila.

The giant extracellular hexagonal bilayer hemoglobin (HBL-Hb) of the deep-sea hydrothermal vent tube worm Riftia pachyptila is able to transport simultaneously O(2) and H(2)S in the blood from the gills to a specific organ: the trophosome that harbors sulfide-oxidizing endosymbionts. This vascular HBL-Hb is made of 144 globins from which four globin types (A1, A2, B1, and B2) coevolve. The H(2)S is bound at a specific location (not on the heme site) onto two of these globin types. In order to understand how such a function emerged and evolved in vestimentiferans and other related annelids, six partial cDNAs corresponding to the six globins known to compose the multigenic family of R. pachyptila have been identified and sequenced. These partial sequences (ca. 120 amino acids, i.e., 80% of the entire protein) were used to reconstruct molecular phylogenies in order to trace duplication events that have led to the family organization of these globins and to locate the position of the free cysteine residues known to bind H(2)S. From these sequences, only two free cysteine residues have been found to occur, at positions Cys + 1 (i.e., 1 a.a. from the well-conserved distal histidine) and Cys + 11 (i.e., 11 a.a. from the same histidine) in globins B2 and A2, respectively. These two positions are well conserved in annelids, vestimentiferans, and pogonophorans, which live in sulfidic environments. The structural comparison of the hydrophobic environment that surrounds these cysteine residues (the sulfide-binding domain) using hydrophobic cluster analysis plots, together with the cysteine positions in paralogous strains, suggests that the sulfide-binding function might have emerged before the annelid radiation in order to detoxify this toxic compound. Moreover, globin evolutionary rates are highly different between paralogous strains. This suggests that either the two globin subfamilies involved in the sulfide-binding function (A2 and B2) have evolved under strong directional selective constraints (negative selection) and that the two other globins (A1 and B1) have accumulated more substitutions through positive selection or have evolved neutrally after a relaxation of selection pressures. A likely scenario on the evolution of this multigenic family is proposed and discussed from this data set.

Amino Acid Sequence↗

PubMed1997

EM algorithms without missing data.

Most problems in computational statistics involve optimization of an objective function such as a loglikelihood, a sum of squares, or a log posterior function. The EM algorithm is one of the most effective algorithms for maximization because it iteratively transfers maximization from a complex function to a simple, surrogate function. This theoretical perspective clarifies the operation of the EM algorithm and suggests novel generalizations. Besides simplifying maximization, optimization transfer usually leads to highly stable algorithms with well-understood local and global convergence properties. Although convergence can be excruciatingly slow, various devices exist for accelerating it. Beginning with the EM algorithm, we review in this paper several optimization transfer algorithms of substantial utility in medical statistics.

Algorithms↗

PubMed1994

Linkage disequilibrium patterns vary with chromosomal location: a case study from the von Willebrand factor region.

Linkage disequilibrium analysis has been used as a tool for analyzing marker order and locating disease genes. Under appropriate circumstances, disequilibrium patterns reflect recombination events that have occurred throughout a population's history. As a result, disequilibrium mapping may be useful in genomic regions of < 1 cM where the number of informative meioses needed to detect recombinant individuals within pedigrees is exceptionally high. Its utility for refining target areas for candidate disease genes before initiating chromosomal walks and cloning experiments will be enhanced as the relationship between linkage disequilibrium and physical distance is better understood. To address this issue, we have characterized linkage disequilibrium in a 144-kb region of the von Willebrand factor gene on chromosome 12. Sixty CEPH and 12 von Willebrand disease families were genotyped for five PCR-based markers, which include two microsatellite repeats and three single-base-pair substitutions. Linkage disequilibrium and physical distance between polymorphisms are highly correlated (rm = -.76; P < .05) within this region. None of the five markers showed significant disequilibrium with the von Willebrand disease phenotype. The linkage disequilibrium/physical distance relationship was also analyzed as a function of chromosomal location for this and eight previously characterized regions. This analysis revealed a general trend in which linkage disequilibrium dissipates more rapidly with physical distance in telomeric regions than in centromeric regions. This trend is consistent with higher recombination rates near telomeres.

Alleles↗

PubMed2005

Markov modelling of immunological and virological states in HIV-1 infected patients.

The purpose of this study was to evaluate the evolution of HIV infected patients and to bring out some significant factors associated with this pathology. The main criteria revealing the State of illness is viral load measurement (VL). However the CD4 lymphocytes also represent an important marker as these reflect the State of the immune reservoir. Many studies have been carried out in this field and different models have been proposed with a view to a better understanding of this disease. Multi State Markov models defined in terms of CD4 counts, or in terms of viral load, have proved to be very useful tools for modelling HIV disease progression. The model we have developed in this study is based on both the CD4 lymphocytes counts and VL. Markov models are characterized by transition intensities. In this paper we explored several structures in succession. First, we used a homogeneous continuous time Markov process with four states defined by crossed values of CD4 and VL in a given patient at a given time. Then, the effect of certain covariates on the infection process was introduced into the model via the transition intensity functions, as with a Cox regression model. Since the hypothesis of homogeneity may be unrealistic in certain cases, we also considered piecewise homogeneous Markov models. Finally, the effects of covariates and time were combined in a piecewise homogeneous model with a covariate. We applied these methods to data from 1313 HIV-infected patients included in the NADIS cohort.

Age Factors↗

PubMed2001

Map Manager QTX, cross-platform software for genetic mapping.

Map Manager QTX (QTX) is software for analysis of genetic mapping experiments in experimental plants and animals. It includes functions for mapping both Mendelian and quantitative trait loci. QTX is an enhanced version of Map Manager QT, rewritten with the aid of cross-platform libraries (XVT, Boulder Software Foundry, Inc.), which allow it to be compiled for multiple computer platforms. It currently is distributed for Microsoft Windows and Mac OS and is available at http://mapmgr.roswellpark.org/mmQTX.html.

Animal Population Groups↗

PubMed2004

Ribosomal protein-sequence block structure suggests complex prokaryotic evolution with implications for the origin of eukaryotes.

Amino acid sequence alignments of orthologous ribosomal proteins found in Bacteria, Archaea, and Eukaryota display, relative to one another, an unusual segment or block structure, with major evolutionary implications. Within each of the prokaryotic phylodomains the sequences exhibit substantial similarity, but cross-domain alignments break up into (a) universal blocks (conserved in both phylodomains), (b) bacterial blocks (unalignable with any archaeal counterparts), and (c) archaeal blocks (unalignable with any bacterial counterparts). Sequences of those eukaryotic cytoplasmic riboproteins that have orthologs in both Bacteria and Archaea, exclusively match the archaeal block structure. The distinct blocks do not correlate consistently with any identifiable functional or structural feature including RNA and protein contacts. This phylodomain-specific block pattern also exists in a number of other proteins associated with protein synthesis, but not among enzymes of intermediary metabolism. While the universal blocks imply that modern Bacteria and Archaea (as defined by their translational machinery) clearly have had a common ancestor, the phylodomain-specific blocks imply that these two groups derive from single, phylodomain-specific types that came into existence at some point long after that common ancestor. The simplest explanation for this pattern would be a major evolutionary bottleneck, or other scenario that drastically limited the progenitors of modern prokaryotic diversity at a time considerably after the evolution of a fully functional translation apparatus. The vast range of habitats and metabolisms that prokaryotes occupy today would thus reflect divergent evolution after such a restricting event. Interestingly, phylogenetic analysis places the origin of eukaryotes at about the same time and shows a closer relationship of the eukaryotic ribosome-associated proteins to crenarchaeal rather than euryarchaeal counterparts.

Amino Acid Sequence↗

PubMed2005

Sampling plans for fitting the psychometric function.

Research on estimation of a psychometric function psi has usually focused on comparing alternative algorithms to apply to the data, rarely addressing how best to gather the data themselves (i.e., what sampling plan best deploys the affordable number of trials). Simulation methods were used here to assess the performance of several sampling plans in yes-no and forced-choice tasks, including the QUEST method and several variants of up-down staircases and of the method of constant stimuli (MOCS). We also assessed the efficacy of four parameter estimation methods. Performance comparisons were based on analyses of usability (i.e., the percentage of times that a plan yields usable data for the estimation of all the parameters of psi) and of the resultant distributions of parameter estimates. Maximum likelihood turned out to be the best parameter estimation method. As for sampling plans, QUEST never exceeded 80% usability even when 1000 trials were administered and rendered accurate estimates of threshold but misestimated the remaining parameters. MOCS and up-down staircases yielded similar and acceptable usability (above 95% with 400-500 trials) and, although neither type of plan allowed estimating all parameters with optimal precision, each type appeared well suited to estimating a distinct subset of parameters. An analysis of the causes of this differential suitability allowed designing alternative sampling plans (all based on up-down staircases) for yes-no and forced-choice tasks. These alternative plans rendered near optimal distributions of estimates for all parameters. The results just described apply when the fitted psi has the same mathematical form as the actual psi generating the data; in case of form mismatch, all parameters except threshold were generally misestimated but the relative performance of all the sampling plans remained identical. Detailed practical recommendations are given.

Algorithms↗

PubMed2002

Long-term microclimatic stress causes rapid adaptive radiation of kaiABC clock gene family in a cyanobacterium, Nostoc linckia, from "Evolution Canyons" I and II, Israel.

Cyanobacteria are the only prokaryotes known thus far possessing regulation of physiological functions with approximate daily periodicity, or circadian rhythms, that are controlled by a cluster of three genes, kaiA, kaiB, and kaiC. Here we demonstrate considerably higher genetic polymorphism and extremely rapid evolution of the kaiABC gene family in a filamentous cyanobacterium, Nostoc linckia, permanently exposed to the acute natural environmental stress in the two microsite evolutionary models known as "Evolution Canyons," I (Mount Carmel) and II (Upper Galilee) in Israel. The family consists of five distinct subfamilies (kaiI-kaiV) comprising at least 20 functional genes and pseudogenes. The obtained data suggest that the duplications of kai genes have adaptive significance, and some of them are evolutionarily quite recent (approximately 80,000 years ago). The observed patterns of within- and between-subfamily polymorphisms indicate that positive diversifying, balancing, and purifying selections are the principal driving forces of the kai gene family's evolution.

Bacterial Proteins↗

PubMed2002

On the joint analysis of longitudinal responses and early discontinuation in randomized trials.

Our focus is on the joint analysis of longitudinal nonnormal responses and early discontinuation in (pre)-clinical trials. Separate models are fitted to the two series (response and discontinuation) to account for covariate and time effects. The serial dependence and the dependence between response and drop-out are also modeled. This is done using particular dependence functions, called copulas. Copulas are used to create a joint distribution with given marginal distributions. Applications are given for the analysis of heart rate/morbidity in toxicology and pain severity/intake of rescue medications in a trial on migraine. Using copulas, the level of dependence between two variables remains invariant to changes in the marginal distribution of either variable. This proves interesting in modeling the association in a longitudinal setting when responses change over time.

Algorithms↗

PubMed2004

Patterns of MHC selection in African mole-rats, family Bathyergidae: the effects of sociality and habitat.

African mole-rats are a family of rodents exhibiting an eclectic range of social behaviour and occupying a variety of habitat types. These differences are likely to impact upon the risk of parasite transmission and virulence, with increasing sociality predicted to correspond to an increased risk of transmission. We investigate these factors by analysing the major histocompatibility complex (MHC), a set of genes responsible for encoding highly variable intermediaries of the vertebrate adaptive immune response. To this end we assessed selection at exons 2 and 3 of the MHC class II DQalpha1 gene of four African mole-rat species representing a range of social behaviours. We demonstrate that: (i) the overall pattern of selection at these exons differentiates according to the predicted function of different regions, with the presence of positive selection indicating the likely influence of host-parasite coevolution; and (ii) contrary to the often observed and predicted positive correspondence between sociality and the risk of parasite transmission, two highly social African mole-rat species in fact appear to have comparatively weak positive selection, suggesting diminished host immunity and thus a low overall risk of parasite transmission.

Africa↗

PubMed2004

The identification of seniors at risk screening tool: further evidence of concurrent and predictive validity.

OBJECTIVES: To evaluate the validity of the Identification of Seniors at Risk (ISAR) screening tool for detecting severe functional impairment and depression and predicting increased depressive symptoms and increased utilization of health services. SETTING: Four university-affiliated hospitals in Montreal. DESIGN: Data from two previous studies were available: Study 1, in which the ISAR scale was developed (n=1,122), and Study 2, in which it was used to identify patients for a randomized trial of a nursing intervention (n=1,889 with administrative data, of which 520 also had clinical data). PARTICIPANTS: Patients aged 65 and older who were to be released from an emergency department (ED). MEASUREMENTS: Baseline validation criteria included premorbid functional status in both studies and depression in Study 2 only. Increase in depressive symptoms at 4-month follow-up was assessed in Study 2. Information on health services utilization during the 5 months after the ED visit (repeat ED visits and hospitalization in both studies, visits to community health centers in Study 2) was available by linkage with administrative databases. RESULTS: Estimates of the area under the receiver operating characteristic curve (AUC) for concurrent validity of the ISAR scale for severe functional impairment and depression ranged from 0.65 to 0.86. Estimates of the AUC for predictive validity for increased depressive symptoms and high utilization of health services ranged from 0.61 to 0.71. CONCLUSION: The ISAR scale has acceptable to excellent concurrent and predictive validity for a variety of outcomes, including clinical measures and utilization of health services.

Activities of Daily Living↗

PubMed1994

Health insurance coverage among the elderly.

The research reported in this paper examines the decision to have private health insurance by elderly Medicare enrollees. Models allowing both stimultaneity and a joint error structure between health insurance and use of medical care are considered. We find that common unobserved variables underlying the joint errors are important determinants in the decision to purchase private health insurance. Simultaneity is present only between the decision to have private health insurance and the probability of visiting a doctor. Health status and functional limitations are important determinants of the decision to have private health insurance in addition to Medicare coverage. Other personal characteristics (age, sex, race and education), as well as household income, Medicaid enrollment, and the employment of a family member are also found to be related to the decision to have private health insurance.

Activities of Daily Living↗

PubMed1997

Learning and forgetting processes in Parkinson's disease: a model-based approach to disentangling storage, retention and retrieval contributions.

Learning and forgetting a prose passage was studied in 20 patients with Parkinson's disease and in 20 normal control subjects by means of stochastic models, with the aim of identifying the learning and retaining abilities that are affected by Parkinson's disease. Results suggested that Parkinson's disease patients are impaired in developing automatic processing both during learning and retaining, while functions that require active attention are spared. The automatic/intentional dissociation, which is the hallmark of motor disturbance in Parkinson's disease, extends to memory abilities, and, on the grounds of neuroanatomical, neurochemical and neurophysiological correlates, suggests that the memory deficit in Parkinson's disease may be contingent on a dysfunction of the medial prefrontal-cingulate cortex.

Aged↗

PubMed2002

Influencing factors of place of death among home care patients with cancer in Taiwan.

Multiple factors, including personal and cultural values, physical and medical factors, and various healthcare systems' forces, influence the place of death of patients with cancer. The purpose of this retrospective chart audit study was to examine the influence of sociodemographic factors, family support, patient functioning, and care needs on the place of death for patients with cancer served by a home care program in Taiwan. Among the 264 study patients, 182 (69%) died at home and 82 (31%) died in the hospital. Significant differences were found between patients dying at home or in a hospital predominantly in the categories of patient functioning and care needs. From the multivariate logistic regression model, home care patients with cancer who were never rehospitalized, who received more home care visits, and who were referred to home care services at the greatest functionally dependent status and with pain were more likely to die at home. Overall, this model could accurately classify 78% of the place of death, which is higher than other published studies. Understanding factors that influence place of death of terminally ill patients with cancer allow healthcare professionals to modify healthcare systems and tailor effective interventions to help patients die at the place they prefer.

Adolescent↗

PubMed2006

Decoding movement intent from human premotor cortex neurons for neural prosthetic applications.

Primary motor cortex (M1), a key region for voluntary motor control, has been considered a first choice as the source of neural signals to control prosthetic devices for humans with paralysis. Less is known about the potential for other areas of frontal cortex as prosthesis signal sources. The frontal cortex is widely engaged in voluntary behavior. Single-neuron recordings in monkey frontal cortex beyond M1 have readily identified activity related to planning and initiating movement direction, remembering movement instructions over delays, or mixtures of these features. Human functional imaging and lesion studies also support this role. Intraoperative mapping during deep brain stimulator placement in humans provides a unique opportunity to evaluate potential prosthesis control signals derived from nonprimary areas and to expand our understanding of frontal lobe function and its role in movement disorders. This study shows that recordings from small groups of human prefrontal/premotor cortex neurons can provide information about movement planning, production, and decision-making sufficient to decode the planned direction of movement. Thus, additional frontal areas, beyond M1, may be valuable signal sources for human neuromotor prostheses.

Action Potentials↗

PubMed1995

Generalizations of current status data with applications.

In estimation of a survival function, current status data arises when the only information available on individuals is their survival status at a single monitoring time. Here, we briefly review extensions of this form of data structure in two directions: (i) doubly censored current status data, where there is incomplete information on the origin of the failure time random variable, and (ii) current status information on more complicated stochastic processes. Simple examples of these data forms are presented for motivation.

HIV Infections↗

PubMed1997

Do traditional symptoms of hypothyroidism correlate with biochemical disease?

OBJECTIVE: Hypothyroidism often remains undetected because of the difficulty associating symptoms with disease. To determine the relation between symptoms and biochemical disease, we assessed symptoms and serum thyroid function tests, concurrently, for patients with and without hypothyroidism. DESIGN: Cross-sectional study. SETTING/PATIENTS: Seventy-six newly diagnosed case patients with overt hypothyroidism and 147 matched control patients identified through outpatient laboratories in Michigan and Colorado. MEASUREMENTS AND MAIN RESULTS: Patient symptoms were assessed by questionnaire. Case patients reported a higher proportion of hypothyroid symptoms than did control patients (30.2% vs 16.5%, p < .0001). Univariate analysis identified three significant predictors of an elevated level of thyroid-stimulating hormone (TSH) (p < .05), and 13 symptoms which, when they had changed in the past year, were reported more often by case patients with hypothyroidism than by control patients (p < .005). Individuals reporting changes in 7 or more symptoms were significantly more likely to have hypothyroidism (likelihood ratio [LR] = 8.7, 95% confidence interval [CI] 3.8, 20.2); those reporting changes in 2 or fewer symptoms were less likely to have hypothyroidism (LR = 0.5, 95% CI 0.4, 0.7). CONCLUSIONS: In this sample, the number of hypothyroid symptoms reported was directly related to the level of TSH. The association was stronger when more symptoms were reported. Symptoms that had changed in the past year were more powerful than symptoms reported present at the time of testing. This suggests that traditional symptoms are valuable when deciding which patients to test for hypothyroidism.

Adult↗

PubMed1997

Biologically effective doses in medium dose rate brachytherapy of cancer of the cervix.

The amount of dose reduction on changing from low dose rate (LDR) brachytherapy to medium dose rate (MDR) or high dose rate (HDR) afterloading has been the subject of much debate. The magnitude of reduction depends, together with other possible factors, on two radiobiological parameters: the alpha/beta ratio and the half-time of repair of the relevant tissues. In an attempt to extract these radiobiological parameters for the late rectal complications observed in our previously published clinical results four different schedules using MDR and one using LDR are analyzed. The percentage incidence of complications was a function of increasing biologically effective dose (BED), but would yield nonsense scattergrams if plotted against raw total dose. In addition, for three other published MDR series, three LDR series, and two HDR series, the incidence of rectal complications is plotted against BED to examine the predictive potential of using BED as the surrogate of total dose. Our own results were published in 1996, consisting of 102 patients treated at the LDR of 0.44 Gy/hr and 88 patients treated by four different schedules using an MDR of 1.6-1.7 Gy/hr. Follow-up is at least 3 years in all schedules. The linear quadratic formula including the "g" dose rate factor was used to analyze them, assuming exponential repair of the repairable beta term. First, multivariate and profile likelihood analyses were carried out to obtain estimates of alpha/beta and T1/2 for rectal late responding tissues. Then graphs of incidence of rectal complications vs. BED were constructed, assuming alpha/beta = 3 Gy and T1/2 = 1.5 hr, values which had not been contradicted by the multivariate analysis. Graphs were drawn both for "all grades including mild reactions" (grades 1 + 2 + 3) and for "serious" complications (grade 3 in our system). In addition, other published cervical brachytherapy series were reviewed, with calculation of their BEDs if not published by the authors. It was necessary to review and compare their grading systems, so that "mild and moderate" (grades 1 and 2) could be contrasted with "serious" (grades 3 and 4 or 5 in various systems). Comparisons were made with other published results, including three LDR, three MDR, and two HDR series spanning from 1982 to 1997. The BEDs at which the incidence of rectal complications rose above the arbitrary level of 10% were compared for all three ranges of dose rate. The multivariate analysis gave estimates of alpha/beta and T1/2 which were not significantly different from 3 Gy and 1.5 hr, respectively, so these values were used to compute the BEDs for the subsequent comparisons. It was found that the graphs of incidence of rectal complications for "all grades including mild" agreed rather better between all series than might have been expected, within a provisional (10%) threshold BED of range 100-123 Gy3 (60-74 Gy given as 2 Gy fractionated external beam or as LDR). The dose-response curves diverged above these values, as expected until common grading systems such as SOMA/ LENT become more widely used. For "serious" complications the 10% incidence occurred at a median BED of 140 Gy3 (84 Gy given as 2 Gy fractionated external beam or as LDR), range 124-155 Gy3. The use of BED (or extrapolated response dose), assuming alpha/beta = 3 Gy and T1/2 = 1.5 hr, instead of total dose, enabled incidence of late rectal complications in cervical brachytherapy with LDR, MDR, and HDR to be plotted in a reasonably consistent way. This does not mean that those parameter values have been definitively determined, but they appear to be provisional values that may be of use in comparing the expected effects of new schedules until better values are obtained from greater use of common grading systems.

Brachytherapy↗