Biomedical subjects

N Goldman

Publications and source records attributed to N Goldman.

At least 19 recordsLinked to original sources

PubMed1998

Phylogenetic information and experimental design in molecular systematics.

Despite the widespread perception that evolutionary inference from molecular sequences is a statistical problem, there has been very little attention paid to questions of experimental design. Previous consideration of this topic has led to little more than an empirical folklore regarding the choice of suitable genes for analysis, and to dispute over the best choice of taxa for inclusion in data sets. I introduce what I believe are new methods that permit the quantification of phylogenetic information in a sequence alignment. The methods use likelihood calculations based on Markov-process models of nucleotide substitution allied with phylogenetic trees, and allow a general approach to optimal experimental design. Two examples are given, illustrating realistic problems in experimental design in molecular phylogenetics and suggesting more general conclusions about the choice of genomic regions, sequence lengths and taxa for evolutionary studies.

Animals↗

PubMed1998

PASSML: combining evolutionary inference and protein secondary structure prediction.

MOTIVATION: Evolutionary models of amino acid sequences can be adapted to incorporate structure information; protein structure biologists can use phylogenetic relationships among species to improve prediction accuracy. Results : A computer program called PASSML ('Phylogeny and Secondary Structure using Maximum Likelihood') has been developed to implement an evolutionary model that combines protein secondary structure and amino acid replacement. The model is related to that of Dayhoff and co-workers, but we distinguish eight categories of structural environment: alpha helix, beta sheet, turn and coil, each further classified according to solvent accessibility, i.e. buried or exposed. The model of sequence evolution for each of the eight categories is a Markov process with discrete states in continuous time, and the organization of structure along protein sequences is described by a hidden Markov model. This paper describes the PASSML software and illustrates how it allows both the reconstruction of phylogenies and prediction of secondary structure from aligned amino acid sequences. AVAILABILITY: PASSML 'ANSI C' source code and the example data sets described here are available at http://ng-dec1.gen.cam.ac.uk/hmm/Passml.html and 'downstream' Web pages. CONTACT: P.Lio@gen.cam.ac.uk

Adenylate Kinase↗

PubMed1998

Assessing the impact of secondary structure and solvent accessibility on protein evolution.

Empirically derived models of amino acid replacement are employed to study the association between various physical features of proteins and evolution. The strengths of these associations are statistically evaluated by applying the models of protein evolution to 11 diverse sets of protein sequences. Parametric bootstrap tests indicate that the solvent accessibility status of a site has a particularly strong association with the process of amino acid replacement that it experiences. Significant association between secondary structure environment and the amino acid replacement process is also observed. Careful description of the length distribution of secondary structure elements and of the organization of secondary structure and solvent accessibility along a protein did not always significantly improve the fit of the evolutionary models to the data sets that were analyzed. As indicated by the strength of the association of both solvent accessibility and secondary structure with amino acid replacement, the process of protein evolution-both above and below the species level-will not be well understood until the physical constraints that affect protein evolution are identified and characterized.

Databases, Factual↗

PubMed1998

The use of calendars to measure child illness in health interview surveys.

BACKGROUND: During the past two decades, health interview surveys have become an increasingly common source of information about current morbidity patterns and utilization of health services in developing countries. This study describes a recent effort to enhance the utility of these surveys by incorporating a calendar format. METHODS: A calendar of morbidity and treatment behaviour during the 2-week period prior to interview was implemented in the Guatemalan Survey of Family Health (EGSF), a large-scale sample survey that was fielded in 60 communities in rural Guatemala in 1995. A total of 2872 women aged 18-35 were interviewed and provided information on 3193 children born since 1990. RESULTS: The EGSF calendar data provide estimates of diarrhoeal illness that are consistent with those obtained from more conventional questionnaire designs. However, in contrast to conventional health survey questions, these calendar data: (1) permit a much more complete evaluation of the accuracy of reporting; and (2) offer a richer and more complex description of child illness and treatment behaviour. For example, the results demonstrate that even the preferred 2-week recall period suffers from underreporting of diarrhoeal illness, that the majority of children with diarrhoea experience at least one additional symptom, and that mothers assess severity of diarrhoea from the type and number of accompanying symptoms. CONCLUSIONS: The findings indicate that additional implementation and evaluation of calendar formats is warranted in order to provide the most useful and accurate data possible at relatively low cost.

Adolescent↗

PubMed1998

Models of molecular evolution and phylogeny.

Phylogenetic reconstruction is a fast-growing field that is enriched by different statistical approaches and by findings and applications in a broad range of biological areas. Fundamental to these are the mathematical models used to describe the patterns of DNA base substitution and amino acid replacement. These may become some of the basic models for comparative genome research. We discuss these models, including the analysis of observed DNA base and amino acid mutation patterns, the concept of site heterogeneity, and the incorporation of structural biology data, all of which have become particularly important in recent years. We also describe the use of such models in phylogenetic reconstruction and statistical methods for the comparison of different models.

Amino Acid Substitution↗

PubMed1997

Misclassification bias in estimates of bereavement effects.

Prospective studies that examine marital status differences in health and mortality frequently fail to update information on marital status in statistical models. The authors illustrate how the resulting misclassification of marital status can produce substantial bias in estimates of bereavement effects associated with widowhood. They use as their main source of data the Longitudinal Study of Aging (LSOA), 1984-1990, a national survey of persons aged 70 years and older. The estimates are based primarily on 3,192 respondents who were married and cohabiting with their spouses at the time of the baseline survey and who could be matched to their spouses' records. Comparisons of widowhood status derived from matched spouse records with reported marital status recorded in LSOA interviews demonstrate that reliance on interview information leads to substantial misclassification of marital status. Results from survival models indicate that estimates of marital status effects are sensitive to whether and how marital status is updated after baseline interviews. For example, updating marital status in hazard models from interview information alone indicates a protective effect of widowhood, whereas classifying widowhood on the basis of spouses' death records reveals a significant bereavement effect (relative mortality risks between 1.3 and 1.4).

Aged↗

PubMed1997

Molecular characterization and ultrastructural localization of Plasmodium falciparum Hsp 60.

Heat shock proteins (Hsp) are a group of highly conserved proteins which are widely represented phylogenetically. Genes for members of the Hsp 70, 90 and 60 families have been cloned from the human malaria parasite Plasmodium falciparum. In this study, we have cloned and expressed the P. falciparum Hsp 60 (PfHsp60) in E. coli. The sequence analysis identified a previously unknown intron of 257 bp beginning after the nucleotide 142 in the coding sequence. Antisera raised against the recombinant PfHsp60 was employed in immunoprecipitation studies with biosynthetically labeled parasite extracts to investigate regulation of expression of PfHsp60 at various temperatures. In contrast to the three to four fold accumulation of PfHsp60 transcripts in heat shocked parasites (37-40 degrees C), the expression of PfHsp60 was not induced in the blood stages of P. falciparum. On the other hand, the effect of heat induction on PfHsp70 was seen both at the level of specific mRNA and protein. In these studies we also observed co-immunoprecipitation of a number of other cellular proteins suggesting possible interaction with PfHsp60. Immunofluorescence analysis indicated the presence of PfHsp60 in the cytoplasm of all the various stages of the parasite. In addition, immunoelectron microscopic analysis distinctly localized PfHsp60 in the mitochondrion of P. falciparum. This study suggests that different mechanisms are involved in the regulation of expression of various members of the heat shock proteins in the parasite.

Animals↗

PubMed1997

Antibody response to influenza immunization in patients after heart transplantation.

The aim of this study was to evaluate post-heart transplantation (Htx) response to two-dose and three-dose influenza vaccine. Hemagglutination inhibition antibodies were monitored in HTx recipients immunized twice (n = 25) or three times (n = 17), and non-HTx controls (n = 8) once, with inactivated influenza vaccine. Post-first dose protective antibody titers (> or = 1:40) were demonstrated in 9/25 (36%) for A/Singapore/ (H1N1), 5/25 (20%) for A/Shanghai/(H3N2) and 2/25 (8%) for B/Yamagata compared with 4/8 (50%), 6/8 (75%) and 2/8 (25%), respectively, for controls. Post-second dose protective titers remained low, increasing following the third dose to 71%, 65% and 29%, respectively. The abnormally low antibody responses of HTx recipients to one-dose and two-dose influenza vaccine can be overcome by a third dose.

Adolescent↗

PubMed1997

The treatment of relapsed or refractory intermediate grade non-Hodgkin's lymphoma with autologous bone marrow transplantation followed by cyclosporine and interferon.

In an effort to decrease the relapse rate following autologous bone marrow transplantation for non-Hodgkin's lymphoma, patients were given cyclosporine and interferon following autologous marrow transplantation. Forty patients with intermediate grade non-Hodgkin's lymphoma that was relapsed or refractory to standard chemotherapy underwent autologous marrow transplantation. The preparative regimen consisted of cyclophosphamide 6.8 g/m2, etoposide 1600 mg/m2, and carmustine 400 mg/m2 over 4 days followed by reinfusion of bone marrow. Intravenous cyclosporine was started on day -1 as a 16 mg/kg loading dose followed by 3.6 mg/kg/day for 28 days after transplant. Patients were begun on alpha-interferon (starting dose, 0.5 million units s.c. every other day) following platelet engraftment (median day 24 post-transplant) and continued on 1.5 million units s.c. daily for 2 years. Regimen-related toxicities resulted in four (10%) deaths. Twenty-one (53%) patients developed marked erythema of the palms, soles, and arms. Biopsies of the erythema were consistent with grade I GVHD. Patients who did not develop rashes were not biopsied. The erythema persisted for a median of 10 days and resolved in all cases without treatment. Visceral GVHD was not apparent. All patients have been followed for a median of 24 months (range 12-54 months). To date, only five patients (13%) have relapsed after bone marrow transplant. Multivariant analysis could not identify risk factors for relapse post-transplant. Disease-free survival of all patients is 77% (95% confidence interval, 67-93%). The results of this pilot study suggest that the administration of cyclosporine and interferon may decrease the relapse rate of relapsed/refractory non-Hodgkin's lymphoma following autologous bone marrow transplantation.

Adolescent↗

PubMed1996

Using evolutionary trees in protein secondary structure prediction and other comparative sequence analyses.

Previously proposed methods for protein secondary structure prediction from multiple sequence alignments do not efficiently extract the evolutionary information that these alignments contain. The predictions of these methods are less accurate than they could be, because of their failure to consider explicitly the phylogenetic tree that relates aligned protein sequences. As an alternative, we present a hidden Markov model approach to secondary structure prediction that more fully uses the evolutionary information contained in protein sequence alignments. A representative example is presented, and three experiments are performed that illustrate how the appropriate representation of evolutionary relatedness can improve inferences. We explain why similar improvement can be expected in other secondary structure prediction methods and indeed any comparative sequence analysis method.

Amino Acid Sequence↗

PubMed1996

Combining protein evolution and secondary structure.

An evolutionary model that combines protein secondary structure and amino acid replacement is introduced. It allows likelihood analysis of aligned protein sequences and does not require the underlying secondary (or tertiary) structures of these sequences to be known. One component of the model describes the organization of secondary structure along a protein sequence and another specifies the evolutionary process for each category of secondary structure. A database of proteins with known secondary structures is used to estimate model parameters representing these two components. Phylogeny, the third component of the model, can be estimated from the data set of interest. As an example, we employ our model to analyze a set of sucrose synthase sequences. For the evolution of sucrose synthase, a parametric bootstrap approach indicates that our model is statistically preferable to one that ignores secondary structure.

Amino Acid Sequence↗

PubMed1996

Prenatal and delivery care and childhood immunization in Guatemala: do family and community matter?

In this paper we investigate family choices about pregnancy-related care and the use of childhood immunization. Estimates obtained from a multilevel logistic model indicate that use of formal (or "modern") health services differs substantially by ethnicity, by social and economic factors, and by availability of health services. The results also show that family and community membership are very important determinants of the use of health care, even in the presence of controls for a large number of observed characteristics of individuals, families, and communities.

Child, Preschool↗

PubMed1995

Marital status and health among the elderly.

Many studies have documented a longevity advantage for married persons relative to their unmarried counterparts in all age groups. However, these studies have failed to determine whether the advantage experienced by married elderly persons arises mostly from selection and causal processes which operated at younger ages. This paper employs data from the Longitudinal Study of Aging (1984-1990) to explore whether marital status continues to exert any influence on health and mortality at the older ages. In the presence of an extensive set of controls for health status at the baseline survey, a series of logistic models are used to determine: (1) the magnitude of marital status effects on disability and on mortality, among older males and older females; and (2) the extent to which the social environment and economic status of the elderly can account for the existing disability and mortality differences by marital status.

Activities of Daily Living↗

PubMed1995

Human immunodeficiency virus type 2 (HIV-2) env gene analysis: prediction of glycoprotein epitopes important for heterotypic neutralization and evidence for three genotype clusters within the HIV-2a subtype.

The env gene sequences of ten tissue-culture-adapted human immunodeficiency virus type 2 (HIV-2) isolates from West African patients were determined. Alignment and comparison of the gene sequences and putative translation products with database sequences revealed 11-29% diversity at the nucleotide level and 15-31% variation at the protein level. From analysis of glycoproteins of HIV-2 strains sensitive and resistant to neutralization by HIV-1 antisera, five regions were identified as putative targets for cross-neutralizing antibody. The HIV-2 equivalent of the HIV-1 V3 loop was not included in this number. However, three of the HIV-2 peptides aligned with regions identified as targets for broad neutralization of HIV-1 strains. These were the V2 and CD4-binding domains of gp120 and the Kennedy domain in gp41. Phylogenetic analysis of the env gene sequences, together with HIV-2 env gene sequences published in the Los Alamos database, support the identification of two distinct HIV-2 subtypes, HIV-2a and HIV-2b. The new sequences are located within the HIV-2a subtype and allow prediction of at least three genotypes, designated I-III. Some correlation of genotype with geographical origin of isolates was noted. Genotype I viruses originate from Guinea Bissau and group II viruses mainly originate from The Gambia. One isolate from Guinea Bissau, HIV-2CAM4, appears phylogenetically older than other viruses in the HIV-2a subtype. The possible implications of this in the light of epidemiological findings in Guinea Bissau are discussed.

Amino Acid Sequence↗

PubMed1994

Social factors and health: the causation-selection issue revisited.

Since social scientists rarely have access to experimental data, they rely heavily upon observational studies. As a consequence, their attempts to make causal inferences about the effects of social factors--such as occupation or marital status--on health are plagued by potential selection problems. Some researchers have addressed this selection-causation problem on the basis of the presence or absence of a particular aggregate pattern of health status. The rationale underlying this approach derives from the investigators' hypotheses that the presence of selection would lead to a particular type of pattern that is distinct from the pattern that would result in the absence of selection. Although intuitively appealing, this strategy appears to be seriously flawed. The essential weakness is that the range of patterns that can result from selection is often much broader than researchers have speculated.

Causality↗

PubMed1994

Variance to mean ratio, R(t), for poisson processes on phylogenetic trees.

The ratio of expected variance to mean, R(t), of numbers of DNA base substitutions for contemporary sequences related by a "star" phylogeny is widely seen as a measure of the adherence of the sequences' evolution to a Poisson process with a molecular clock, as predicted by the "neutral theory" of molecular evolution under certain conditions. A number of estimators of R(t) have been proposed, all predicted to have mean 1 and distributions based on the chi 2. Various genes have previously been analyzed and found to have values of R(t) far in excess of 1, calling into question important aspects of the neutral theory. In this paper, I use Monte Carlo simulation to show that the previously suggested means and distributions of estimators of R(t) are highly inaccurate. The analysis is applied to star phylogenies and to general phylogenetic trees, and well-known gene sequences are reanalyzed. For star phylogenies the results show that Kimura's estimators ("The Neutral Theory of Molecular Evolution," Cambridge Univ. Press, Cambridge, 1983) are unsatisfactory for statistical testing of R(t), but confirm the accuracy of Bulmer's correction factor (Genetics 123: 615-619, 1989). For all three nonstar phylogenies studied, attained values of all three estimators of R(t), although larger than 1, are within their true confidence limits under simple Poisson process models. This shows that lineage effects can be responsible for high estimates of R(t), restoring some limited confidence in the molecular clock and showing that the distinction between lineage and molecular clock effects is vital.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1994

Phylogenetic analysis of the rpoB gene from the plastid-like DNA of Plasmodium falciparum.

Malaria and other Apicomplexan parasites harbour two extrachromosomal DNAs. One is mitochondrial and the other is a 35-kb circle with some plastid-like features but whose provenance and function is unknown. In addition to genes for rRNAs, tRNAs and ribosomal proteins, the 35-kb circular DNA of Plasmodium falciparum carries an rpoBC operon which encodes subunits of a eubacteria-like RNA polymerase. The phylogenetic analysis of the complete rpoB sequence presented here supports our inference that the 35-kb circle is the remnant of a plastid genome.

Amino Acid Sequence↗

PubMed1994

Health cards, maternal reports and the measurement of immunization coverage: the example of Guatemala.

Immunization against major childhood diseases has been an essential component of health policies in developing countries. However, despite its importance and the efforts invested by many organizations in promoting immunization programs, consistent and accurate measurement of immunization coverage has not yet been achieved. In this paper, we explore the implications of alternative methods of measuring immunization coverage rates in Guatemala, using data from the 1987 Encuesta Nacional de Salud Materno Infantil, and we consider the dangers of making inferences about levels and trends in coverage from cross-sectional data. The results indicate that (1) service statistics may well lead to overestimates of coverage; (2) survey estimates derived from health cards can also produce severely biased estimates; and (3) in spite of problems associated with maternal recall, mothers' reports of their children's vaccination status probably result in substantially improved estimates of immunization coverage.

Bias↗