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PubMed2003

Keeping data continuous when analyzing the prognostic impact of a tumor marker: an example with cathepsin D in breast cancer.

The prognostic value of cathepsin D has been recently recognized, but as many quantitative tumor markers, its clinical use remains unclear partly because of methodological issues in defining cut-off values. Guidelines have been proposed for analyzing quantitative prognostic factors, underlining the need for keeping data continuous, instead of categorizing them. Flexible approaches, parametric and non-parametric, have been proposed in order to improve the knowledge of the functional form relating a continuous factor to the risk. We studied the prognostic value of cathepsin D in a retrospective hospital cohort of 771 patients with breast cancer, and focused our overall survival analysis, based on the Cox regression, on two flexible approaches: smoothing splines and fractional polynomials. We also determined a cut-off value from the maximum likelihood estimate of a threshold model. These different approaches complemented each other for (1) identifying the functional form relating cathepsin D to the risk, and obtaining a cut-off value and (2) optimizing the adjustment for complex covariate like age at diagnosis in the final multivariate Cox model. We found a significant increase in the death rate, reaching 70% with a doubling of the level of cathepsin D, after the threshold of 37.5 pmol mg(-1). The proper prognostic impact of this marker could be confirmed and a methodology providing appropriate ways to use markers in clinical practice was proposed.

Aged↗

PubMed2004

Parental phenotypes in family-based association analysis.

Family-based association designs are popular, because they offer inherent control of population stratification based on age, sex, ethnicity, and environmental exposure. However, the efficiency of these designs is hampered by current analytic strategies that consider only offspring phenotypes. Here, we describe the incorporation of parental phenotypes and, specifically, the inclusion of parental genotype-phenotype correlation terms in association tests, providing a series of tests that effectively span an efficiency-robustness spectrum. The model is based on the between-within-sibship association model presented in 1999 by Fulker and colleagues for quantitative traits and extended here to nuclear families. By use of a liability-threshold-model approach, standard dichotomous and/or qualitative disease phenotypes can be analyzed (and can include appropriate corrections for phenotypically ascertained samples), which allows for the application of this model to analysis of the commonly used affected-proband trio design. We show that the incorporation of parental phenotypes can considerably increase power, as compared with the standard transmission/disequilibrium test and equivalent quantitative tests, while providing both significant protection against stratification and a means of evaluating the contribution of stratification to positive results. This methodology enables the extraction of more information from existing family-based collections that are currently being genotyped and analyzed by use of standard approaches.

Female↗

PubMed2003

A neurodevelopmental model for anorexia nervosa.

This paper integrates genetic and biological data on aetiological risk for anorexia nervosa (AN) with cognitive and psychosocial explanatory models. We have reviewed clinical and basic science data from each of these domains and then used a developmental perspective to formulate a multifactorial threshold model. By positioning interpersonal stress as a central component of this model, psychological, social and biological conceptualisations of AN can be used to generate a data driven, neurodevelopmental hypothesis for the aetiology of this complex disorder.

Adaptation, Psychological↗

PubMed1998

Developmental psychopathology, personality, and temperament: reflections on recent behavioral genetics research.

Personality, temperament, and psychopathology were until recently largely distinct areas of study, each of which emphasized partitioning of heritable and environmental variance. The emergence of the paradigm of developmental psychopathology along with application of multivariate biometric models to behavioral genetic data has defined a second phase of research in these domains. Integrated research has begun to map dimensional liability-threshold models of psychopathology and to evaluate empirically the categorical versus dimensional etiology of traits and disorders. An interesting pattern in the data is that psychopathology is probably not merely an extreme of temperament or personality in many cases. Variations in temperament and personality are now known to be heavily influenced by additive genetic and nonshared environmental factors and to exhibit stable or increasing heritability across development. This pattern holds for some measures of psychopathology but not for others. For example, shared environment effects and decreasing heritability influence much adolescent psychopathology, and comorbid problems in young children appear to be due in part to shared environment effects. Other recent biometric work on the central problem of comorbidity in psychopathology suggests that shared genetic covariation accounts for some specific comorbidities but not others. A third phase of research is now underway, featuring study of specific molecular gene mechanisms by means of linkage and association studies in relation to behavioral phenotypes. Complementary integration of discoveries from biometric behavioral studies and molecular studies is expected to be the norm for the near future.

Adult↗

PubMed1995

Agenesis of permanent maxillary lateral incisors in South Australian twins.

The frequency of agenesis of maxillary lateral incisors (I2) in a sample of South Australian twins was determined, and associations with gender, zygosity, birthweight and dental crown size were investigated. Ten of the 446 twins examined (2.24 per cent) displayed agenesis of one or both I2, a similar frequency to that reported for Australian singletons. Seven of the ten affected individuals were monozygous female twins, including two pairs, while the three affected dizygous twins were each from different male twin pairs. Five pairs of monozygous twins were identified who displayed varying expressions of normal, small, peg-shaped or missing I2. These twin pairs displayed disparate birthweights suggesting they may have been mono-chorionic. These findings are consistent with a multifactorial threshold model linking size and number of I2 with developmental influences modifying phenotypic expression in those monozygous twins whose genetic predisposition places them near to the threshold for agenesis.

Adolescent↗

PubMed1995

A cost analysis of hematopoietic colony-stimulating factors.

The administration of hematopoietic colony-stimulating factors (CSFs) to reduce the severity and duration of neutropenia associated with systemic chemotherapy has become widespread, although the appropriate use of these agents has not yet been fully defined. A cost model based on decision theory is presented for three therapeutic choices in these patients: no CSF, prophylactic CSF, and therapeutic CSF. Baseline probabilities were derived from a prospective, randomized, placebo-controlled trial of G-CSF in patients receiving systemic chemotherapy. Application of the model to institutionally generated cost figures provides comparative estimates of excess cost favoring the prophylactic use of CSFs. Model thresholds were calculated based on sensitivity analysis comparing no CSF to prophylactic CSF, and therapeutic CSF to prophylactic CSF. Guidelines are provided based on this model that are consistent with those adopted by the American Society of Clinical Oncology.

Antineoplastic Agents↗

PubMed1996

The genetical and environmental determination of phally polymorphism in the freshwater snail Bulinus truncatus.

In some species of self-fertile pulmonate snails, two sexual morphs co-occur in natural populations: regular individuals and aphallic individuals that cannot transmit sperm to other snails. Purely aphallic populations therefore reproduce obligatorily by selfing. Understanding the evolution of aphally and selfing in these snails requires a precise knowledge of phally determination. In this paper, we investigate the genetic and environmental determination of aphally in Bulinus truncatus by a survey of the family (offspring) aphally ratio of 233 individuals originating from seven natural populations and a study of the reaction norm of the family aphally ratio to temperature using 60 individuals from 10 selfed lineages of one population. Our results indicate a high genetic variability for the determination of aphally between populations and within some populations, associated with a high level of genetic determination. Our second experiment indicates a significant temperature and lineage effect though no interaction between these two effects. We discuss our results in the framework of threshold models developed for dimorphic traits with polygenic inheritance. We propose that the sexual morph of an individual at a given temperature is determined by a temperature threshold value depending on both the individual genotype and probabilistic processes.

Animals↗

PubMed1999

Discrete threshold versus continuous strength models of perceptual recognition.

Two experiments were designed to test discrete-threshold models of letter and word recognition against models that assume that decision criteria are applied to measures of continuous strength. Although our goal is to adjudicate this matter with respect to broad classes of models, some of the specific predictions for discrete-threshold are generated from Grainger and Jacobs' (1994) Dual-Readout Model (DROM) and some of the predictions for continuous strength are generated from a revised version of the Activation-Verification Model (Paap, Newsome, McDonald, & Schvaneveldt, 1982). Experiment 1 uses a two-alternative forced-choice task that is followed by an assessment of confidence and then a whole report if a word is recognized. Factors are manipulated to assess the presence or magnitude of a neighbourhood-frequency effect, a lexical-bias effect, a word-superiority effect, and a pseudoword advantage. Several discrepancies between DROM's predictions and the obtained data are noted. Both types of models were also used to predict the distribution of responses across the levels of confidence for each individual participant. The predictions based on continuous strength were superior. Experiment 2 used a same-different task and confidence ratings to enable the generation of receiver operating characteristics (ROCs). The shapes of the ROCs are more consistent with the continuous strength assumption than with a discrete threshold.

Cognition↗

PubMed2003

The origin of interlocus sexual conflict: is sex-linkage important?

Sexual conflict has been proposed as a potential selective agent in the evolution of a variety of traits. Here, we present a simple model that investigates the initial conditions under which sex-linked and sex-limited harming alleles can invade a population. In this paper, we expand previous threshold models to study how sex-linkage and sex determination mechanisms affect the spreading conditions of a harming allele. Our models provide new insights into how sexual conflict could originate, showing that in diploid organisms the probability of a new harming allele spreading is independent of both the genetic sex determination system and the dominance relationships. However, the incidence of interlocus sexual conflicts in the initial steps of the invasion critically depends on the inheritance system.

Animals↗

PubMed2003

Minor physical anomalies in schizophrenic patients and normal controls.

The aim of the study is to investigate the rate and topographical pattern of minor physical anomalies in schizophrenic patients and normal subjects and determine their value in predicting the patient-control status. Seventy-six schizophrenic inpatients (43 men, 33 women) and 82 normal control subjects (42 men, 40 women) were examined for minor physical anomalies on the Waldrop scale. Schizophrenics showed a higher rate for almost all examined anomalies, the differences reaching statistical significance for six of them: fine electric hair, epicanthus, high/steepled palate, tongue with smooth/rough spots, third toe the second, and big gap between I and II toes. They have significantly higher values for 5 out of 6 body regions and for the total anomalies score. Anomalies in schizophrenics show higher prevalence in the craniofacial complex than the periphery, but the periphery is also considerably stigmatized. Seven anomalies distinguish patients from controls, classifying correctly 81.6% of the patients and 82.9% of the controls. Some anomalies show an almost equal rate in the schizophrenics and the controls, while the rate of others is more than 10 times greater in the patients (odds ratios range: 1.0 to 10.9). Viewed within the multifactorial-polygenic threshold model of liability to a disease, minor physical anomalies might reflect a type of neurodevelopmental risk factor, which by interaction with other genetic or environmental factors could result in passing a threshold and producing symptoms of the disorder, at least in one subpopulation of schizophrenics.

Adolescent↗

PubMed1991

Standard setting processes and regulations for environmental contaminants in drinking water: state versus federal needs and viewpoints.

The primary objective of a standard setting process is to arrive at a drinking water concentration at which exposure to a contaminant would result in no known or potential adverse health effect on human health. The drinking water standards also serve as guidelines to prevent pollution of water sources and may be applicable in some cases as regulatory remediation levels. The risk assessment methods along with various decision making parameters are used to establish drinking water standards. For carcinogens classified in Groups A and B by the United States Environmental Protection Agency (USEPA) the standards are set by using nonthreshold cancer risk models. The linearized multistage model is commonly used for computation of potency factors for carcinogenic contaminants. The acceptable excess risk level may vary from 10(-6) to 10(-4). For noncarcinogens, a threshold model approach based on application of an uncertainty factor is used to arrive at a reference dose (RfD). The RfD approach may also be used for carcinogens classified in Group C by the USEPA. The RfD approach with an additional uncertainty factory of 10 for carcinogenicity has been applied in the formulation of risk assessment for Group C carcinogens. The assumptions commonly used in arriving at drinking water standards are human life expectancy, 70 years; average human body weight, 70 kg; human daily drinking water consumption, 2 liters; and contribution of exposure to the contaminant from drinking water (expressed as a part of the total environmental exposure), 20%. Currently, there are over 80 USEPA existing or proposed primary standards for organic and inorganic contaminants in drinking water. Some of the state versus federal needs and viewpoints are discussed.

Carcinogens, Environmental↗

PubMed2004

Dose and schedule as determinants of outcomes in chemotherapy for breast cancer.

Many cytotoxic agents for the adjuvant treatment of breast cancer are available, but they have produced only modest results, even when the tumor burden is low. This relative lack of efficacy may be attributed, in part, to the nonspecificity of the current regimens. Additionally, there is evidence that the chemotherapy doses used in clinical practice are not optimal, which potentially compromises the outcomes when the thresholds of dose intensity are not reached. Variations in treatment underscore the need to return to the basics of chemotherapy administration: dose, schedule, concentration threshold, and therapeutic index. In patients with metastatic breast cancer a clear dose-response curve has been shown with some agents, including anthracyclines. The E-max model, which in its simplest form assumes a direct relation between the dose of a drug and its effect, may be used to improve dosing in the adjuvant treatment of breast cancer. Consistent with this model, threshold effects have been observed in treatment with both anthracyclines and paclitaxel for breast cancer. There is also evidence that using dose-dense schedules may produce better outcomes with some regimens. Maintaining chemotherapy agents at full dose on schedule is crucial to treatment success, especially in adjuvant therapy. Consequently, treatment practices should use both dose intensity and dose compression to increase the likelihood of positive outcomes in patients with breast cancer.

Antineoplastic Agents↗

PubMed1991

Arousal responses to hypertension in lambs: effect of sinoaortic denervation.

Newborn lambs were subjected to hypertensive stimuli of 1-min duration to examine features of hypertension-induced arousal from sleep. Reflex mechanisms involved were studied by performing the same tests after sinoaortic denervation (SAD). In intact lambs, hypertension increased the probability of arousal from both quiet sleep (QS) and rapid-eye-movement (REM) sleep. Hypertension resulted in arousal in 51% (QS) and 50% (REM) of tests. Arousal time was significantly longer in REM (29.3 +/- 0.9 s, mean +/- SE) than in QS (22.6 +/- 0.6 s, P less than 0.01). Arterial oxygen saturation (So2) and partial pressure of oxygen (Po2) measured at the point of arousal, or after 60 s if arousal failed to occur, were unchanged from control values. After SAD hypertension did not increase the probability of arousal. Arousals significantly decreased (P less than 0.001) to 31% (QS) and 10% (REM). These findings indicate that acute hypertension, mediated via arterial baroreceptors, is a potent stimulus for arousal. In intact lambs, the arousal probability increased and arousal time decreased with increasing stimulus strength (1-30 mmHg), but the arousal time difference between QS and REM remained constant. Consideration of these findings in terms of a simple baroreflex threshold model suggests that the slower response in REM sleep is explained by slower neural processes after the achievement of a critical arousal input rather than by a higher threshold for baroreceptor input in this state.

Aging↗

PubMed1986

New look at Bloch's law for contrast.

It has been commonly reported that the temporal integration of grating contrast proceeds more slowly as spatial frequency is increased. Such results have been based on the critical duration for sensitivity to contrast pulses varying in duration, but the analyses have not assumed full integration at short durations and have neglected the effects of probability summation over time. To take such effects into account, we discuss a class of analytical models based on nonlinear temporal integration. On the assumption that the temporal impulse response of the visual system determines contrast integration over time, we develop both a high-threshold model and a signal-detection approach involving multiple and independent nonlinear signal detectors with a time-limited integration span. The redefined critical durations predicted by the models and verified by the data are about 35 msec and vary by no more than 10 msec across spatial frequency. This variation is entirely attributable to a change in the strength of inhibition with spatial frequency, and the analysis implies that the excitatory component is constant at all spatial frequencies, contrary to previous accounts.

Humans↗

PubMed1995

A pilot Swedish twin study of affective illness including hospital- and population-ascertained subsamples: results of model fitting.

We investigated the heritability of liability to affective illness (AI) in twins ascertained through psychiatric hospitalization for AI from the Swedish Psychiatric Twin Registry and from the general population Swedish Twin Registry. Lifetime diagnoses were assessed by mailed questionnaire containing, in self-report format, DSM-III-R criteria for mania and major depression (MD). Jointly analyzing both subsamples using Mx, and assuming a multifactorial threshold model, the best-fitting twin model using narrow diagnostic criteria suggested that the liability to AI could be explained by additive genetic effects, with an estimated heritability of liability of 64%, and individual-specific environment. Using broad criteria, results were similar except that the estimated broad heritability of liability was higher (83%) and due largely to dominance genetic effects. Fitting sex-dependent models suggested that the same genetic and environmental factors influenced liability to AI in men and women to the same degree, although women had a lower threshold of manifestation. These results suggested that in Sweden, AI is a highly heritable syndrome and family resemblance is due largely or entirely to genetic factors.

Adult↗

PubMed1994

The power of the classical twin study to resolve variation in threshold traits.

We explore the power of the twin study to resolve sources of familial resemblance when the data are measured at the binary or ordinal level. Four components of variance were examined: additive genetic, nonadditive genetic, and common and specific environment. Curves are presented to compare the power of the continuous case with those of threshold models corresponding to different prevalences in the population: 1, 5, 10, 25, and 50%. Approximately three times the sample size is needed for equivalent power to the continuous case when the threshold is at the optimal 50%, and this ratio increases to about 10 times when 10% are above threshold. Some power may be recovered by subdividing those above threshold to form three or more ordered classes, but power is determined largely by the lowest threshold. Non-random ascertainment of twins (i) through affected twins and examining their cotwins or (ii) through ascertainment of all pairs in which at least one twin is affected increases power. In most cases, strategy i is more efficient than strategy ii. Though powerful for the rarer disorders, these methods suffer the disadvantage that they rely on prior knowledge of the population prevalence. Furthermore, sampling from hospital cases may introduce biases, reducing their value. A useful approach may be to assess the population with a screening instrument; the power calculations indicate that sampling all concordant and half of the discordant pairs would be efficient, as along as the cost of screening is not too high.

Bias↗

PubMed1993

A model of selective synapse formation in sympathetic ganglia.

In the sympathetic system, neurons from several spinal segments are mapped onto targets in the periphery in a topographically ordered way by means of selective synaptic connections in the superior cervical ganglion. Experimental evidence points to a crucial role for chemoaffinity in establishing this topographic map. Furthermore, rearrangements of synapses after surgical manipulations indicate that this chemoaffinity is not based on rigid "key-and-lock" markers. Our model is used to study how such nonrigid markers may interact with other regulatory factors, including growth-regulating signals and the growth potential of individual neurons. In the model, these latter factors are limiting, so that an increasing number of synaptic contacts decreases the likelihood of further synapse formation. These factors are combined with chemoaffinity using a linear threshold model. The model is robust to parameter changes and reproduces experimental observations with reasonable detail. Simulation results are used to discuss characteristic experimental results, such as the substantial plasticity of the connections seen after partial denervation. A surprisingly small effect of transient hyperinnervation in the model may help explain why final connectivities are similar in two real situations with high and low degrees of transient hyperinnervation (development and adult reinnervation). It is shown that spatial restrictions on post-synaptic neurons (dendrites) may contribute significantly to the segmentally broad innervation of each ganglion cell. Finally, we discuss potential effects of presynaptic neuronal death in systems with a high degree of plasticity.

Animals↗

PubMedDate not supplied

[On parametric stability of gene networks controlling ontogenetic processes].

The problem of evaluating the parametric stability of three models of pro- and eukaryotic gene networks controlling ontogenetic processes has been defined and solved. Experimental plans of testing gene networks for parametric stability based on the method of generalized threshold models were developed and realized as a software application. We examined the "sensitivity" of the functioning modes to random variations of the parameters in the three model systems: the system of developmental control of phage lambda, the subsystem of morphogenetic control of Arabidopsis thaliana flower, and the gene subnetwork controlling early ontogeny in Drosophila melanogaster. The parametric stability was quantitatively assessed for these models.

Animals↗