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Results for “causality”

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At least 1,063 records · Page 59Linked to original sources

PubMed2004

Parametric randomization-based methods for correcting for treatment changes in the assessment of the causal effect of treatment.

We develop parametric maximum likelihood methods to adjust for treatment changes during follow-up in order to assess the causal effect of treatment in clinical trials with time-to-event outcomes. The accelerated failure time model of Robins and Tsiatis relates each observed event time to the underlying event time that would have been observed if the control treatment had been given throughout the trial. We introduce a bivariate parametric frailty model for time to treatment change and time to trial endpoint. Estimating equations which respect the randomization are constructed and compared to maximum likelihood methods in a simulation study. The Concorde trial of immediate versus deferred zidovudine in HIV infection is used as a motivating example and illustration of the methods.

Anti-HIV Agents↗

PubMed2004

Stratification and weighting via the propensity score in estimation of causal treatment effects: a comparative study.

Estimation of treatment effects with causal interpretation from observational data is complicated because exposure to treatment may be confounded with subject characteristics. The propensity score, the probability of treatment exposure conditional on covariates, is the basis for two approaches to adjusting for confounding: methods based on stratification of observations by quantiles of estimated propensity scores and methods based on weighting observations by the inverse of estimated propensity scores. We review popular versions of these approaches and related methods offering improved precision, describe theoretical properties and highlight their implications for practice, and present extensive comparisons of performance that provide guidance for practical use.

Computer Simulation↗

PubMedDate not supplied

Third variable analysis: application to causal sequences among nutrient intake, maternal weight, birthweight, placental weight, and gestation.

We applied a set of procedures, aimed at enhancing the strength of inferences about the direction of causal paths among variables measured at the same time, to foetal and maternal indices recorded at birth and collected for study of the Dutch famine of 1944/5. The analysis of three-variable sets yielded strong inferences about the relations among caloric intake, maternal weight, birthweight, placental weight, and length of gestation. These procedures constitute not only a useful preliminary to the construction of multivariate path models, but produce useful results in their own right.

Birth Weight↗

PubMed2000

Lipostat in the lean rat: evidence for a non-causal relationship between glucocorticoids and leptin levels.

In order to assess the long-term impact of a complete depletion of glucocorticoids on plasma leptin levels, we bilaterally adrenalectomized 20 lean rats, and analysed glucocorticoids and leptin levels for 20 consecutive days. Results demonstrate that the adrenalectomy (ADX) significantly lowered the leptin levels, as compared to sham-operated controls. On the other hand, a significant increase in leptin levels was noticeable from day 1 to day 20 of the experiment in the sham-operated controls, even though corticosterone levels remained stable during that same period. Plasma leptin concentration was proportional to body fat content. These results would indicate a non-causal relationship between glucocorticoids and leptin levels in the context of a lipostat in the lean rat.

Adrenalectomy↗

PubMed1999

Evaluation of cGMP-phosphodiesterase (PDE) subunits for causal association with rod-cone dysplasia 2 (rcd2), a canine model of abnormal retinal cGMP metabolism.

Rod-cone dysplasia types 1 (rcd1; Irish setter) and 2 (rcd2; collie) in dogs are early onset forms of progressive retinal atrophy (PRA) which serve as models of retinitis pigmentosa (RP) in humans. As both rcd1 and rcd2 result from abnormal retinal cGMP metabolism associated with a deficiency in cGMP-phosphodiesterase (PDE) activity, and a nonsense mutation in the PDE6B subunit gene has been shown to cause rcd1, the genes encoding the four subunits of the PDE complex (PDE6A, PDE6B, PDE6G and PDE6D) make compelling candidates for the rcd2 locus. We adopted diverse strategies to evaluate causal association of the four PDE subunit genes with the rcd2 phenotype. Identification in an informative pedigree of obligate recombinations between intragenic polymorphisms within PDE6A and PDE6D and the rcd2 locus unequivocally excludes these two genes. PDE6B was excluded by a breeding strategy demonstrating nonallelism of rcd1 and rcd2. Direct sequencing of PDE6G from an rcd2 -homozygous collie dog revealed no abnormality in the entire genomic sequence. To evaluate cosegregation between PDE6G and rcd2, advantage was taken of prior knowledge that PDE6G and Galactokinase 1 (GALK1) localize to the same canine-rodent somatic hybrid cell line. Linkage analysis using a single nucleotide polymorphism (SNP) in the PDE6G gene, and a (CA)n repeat polymorphism in the GALK1 gene, which were both segregating in an unrelated pedigree, established close linkage of these two genes (theta = 0; Z = 4.21). Identification of obligate recombinations between GALK1 and the rcd2 locus in an informative rcd2 pedigree thus excluded PDE6G as a candidate gene for rcd2; the exclusion distance between GALK1 and rcd2 is at least 0.35 cM. These results therefore exclude the entire set of genes coding for the rod PDE complex as candidates for rcd2.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2000

Causal links between stressful events, coping style, and adolescent symptomatology.

In a longitudinal study, the causal links between different types of stressors, coping styles and adolescent symptomatology were investigated. A total of 94 adolescents and their mothers participated in three annual assessments of critical life events, daily stressors and coping styles. The longitudinal associations between life events, everyday stressors, a dysfunctional coping style and symptomatology were analyzed via a path-analytic model. Critical life events and daily stressors were found to be strongly related over time; however, the type of stressor was not consistently linked with adolescent symptomatology. In contrast, withdrawal, a form of avoidant coping, emerged as a significant predictor of adolescent symptomatology across all times. Further, emotional and behavioral problems led to a time-lagged increase in withdrawal, creating a vicious circle. The results are discussed with reference to the coping-skill deficit model.

Adaptation, Psychological↗

PubMed2000

No confirmation for a causal role of volume-regulated chloride channels in ischemic preconditioning in rabbits.

Volume-regulated chloride channels have recently been proposed to be end-effectors in ischemic preconditioning. The present study attempted to confirm this hypothesis by looking both at cardioprotection and channel activity. In isolated rabbit cardiomyocytes, hypo-osmotic stress (167 mosm/l) induced a current with a magnitude of 2-5 pA/pF at 60 mV. That current could be blocked by the selective chloride channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) or indanyloxyacetic acid 94 (IAA-94), but only at 100 microM and 1 m M respectively. Lower concentrations were not effective. Because the channel-blocking concentrations were toxic in isolated perfused rabbit hearts, as evidenced by cessation of cardiac contraction and massive infarction, neither agent could be tested against preconditioning's anti-infarct effect. NPPB and IAA-94 at 1 microM and 10 microM, respectively (the doses used in a previous report), did not affect coronary flow, heart rate and developed pressure, and also did not prevent the infarct size reduction of ischemic preconditioning with 5 min global ischemia/10 min reperfusion preceding 30 min of regional ischemia and 120 min of reperfusion [11. 4(+/-3.6) and (11.1(+/-3.7)% infarction of risk area, respectively]. The volume-regulated chloride and organic osmolyte channel blocker 4, 4;-diisothiocyanostilbene-2,2;-disulfonic acid (DIDS) at 100 microM blocked the hypo-osmotically induced current in myocytes, but again could not be used, since it induced total cessation of cardiac contraction and reduced infarct size in non-preconditioned hearts. Our data do not confirm a prior study on a causal role for volume-regulated chloride channels in the protection of ischemic preconditioning. This hypothesis remains to be adequately tested.

Animals↗

PubMed2002

On the number of experiments required to find the causal structure of complex systems.

The need to capture the complexity of biological systems in a simpler formalism is the underlying impetus of biological sciences. Understanding the function of many biological complex systems, such as genetic networks or molecular signalling pathways, requires precise identification of the interactions between their individual components. A number of questions in the study of complex systems are then important-in particular, what can be inferred about the interactions in a complex system from an arbitrary set of experiments, and, what is the minimum number of experiments required to characterize the system? This paper shows that the problem of finding the minimal causal structure of a system based on a set of observations is computationally intractable for even moderately sized systems (it is NP-hard), but a reasonable approximation can be found in a relatively short (polynomial) time. Next, it is shown that the number of experiments required to characterize a complex system grows exponentially with the upper bound on the number of immediate upstream influences of each element, but only logarithmically with the number of elements in the system. This makes it possible to study biological systems with extremely large number of interacting elements and relatively sparse interconnections, such as gene regulatory and cell signalling networks. Finally, the construction of a randomized experimental sequence which achieves this bound is discussed.

Animals↗

PubMed1999

Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease.

Rats with unilateral dopamine-denervating lesions sustained a 3-week treatment with a daily l-DOPA dose that is in the therapeutic range for Parkinson's disease. In most of the treated animals, chronic l-DOPA administration gradually induced abnormal involuntary movements affecting cranial, trunk, and limb muscles on the side of the body contralateral to the lesion. This effect was paralleled by an induction of FosB-like immunoreactive proteins in striatal subregions somatotopically related to the types of movements that had been elicited by l-DOPA. The induced proteins showed both regional and cellular colocalization with prodynorphin mRNA. Intrastriatal infusion of fosB antisense inhibited the development of dyskinetic movements that were related to the striatal subregion targeted and produced a local specific downregulation of prodynorphin mRNA. These data provide compelling evidence of a causal role for striatal fosB induction in the development of l-DOPA-induced dyskinesia in the rat and of a positive regulation of prodynorphin gene expression by FosB-related transcription factors.

Animals↗

PubMed1999

The frequency, antecedent events, and causal relationships of neurologic worsening following severe head injury. Executive Committee of the international Selfotel Trial.

Neurologic deterioration observed following head injury is recognized as having a deleterious effect on outcome. The present study examines this occurrence in detail to determine the frequency of these episodes, their antecedent events and causal relationships in order to identify patients who are at risk. Data was collected prospectively from a consecutive series of 427 patients entered into the international trial of the NMDA receptor antagonist Selfotel. Using a definition of neurologic worsening based upon objective criteria, 117 patients were identified who suffered 164 episodes of deterioration. The occurrence of a single episode of neurologic worsening increased mortality by more than five-fold and reduced favorable outcomes (good or moderate on the Glasgow Outcome Scale), by more than 50%. Increased intracranial volume resulting in intracranial hypertension was the single most frequent cause of neurologic worsening. This serves to emphasize the importance of more adequate treatments of intracranial hypertension in improving the outcome of patients with severe head injury.

Adolescent↗

PubMed1996

Causal connection between detoxification enzyme activity and consumption of a toxic plant compound.

Insect herbivores can increase their detoxification activities against a particular plant poison in response to prolonged ingestion of the same compound. For example, larval tobacco hornworms (Manduca sexta) experience a dramatic increase in cytochrome P450 activity against nicotine after ingesting nicotine. While it is generally assumed that this induction process permits increased consumption of toxic plant tissues, we are not aware of any direct experimental support for this assumption. Using a two-tiered approach, we examined the functional significance of P450 induction to M. sexta larvae ingesting a toxic but non-deterrent concentration of nicotine. First, we related the time-course of P450 induction in midgut microsomes to changes in nicotine consumption. When offered a nicotine diet, larvae failed to show a significant increase in consumption before 36 h, which was coincident with the time-course of the induction of midgut P450 activities against aldrin and nicotine. Second, we determined whether inhibiting the induced P450 activities affected nicotine consumption. We found that the increase in nicotine consumption following the induction of nicotine metabolism could be strongly inhibited by treatment with piperonyl butoxide, which by itself did not inhibit consumption. These results provide direct evidence for a causal connection between P450-mediated detoxification activity and consumption of a toxic plant compound.

Animals↗

PubMed1980

Evidence for multiple causality in the development of diabetic hypertriglyceridaemia.

The relationship between varying degrees of insulin deficiency and hypertriglyceridaemia in rats have been examined. Rats were studied 7--10 days after injection with streptozotocin, and plasma glucose concentrations used to classify rats as having either moderate (200--350 mg/dl) or severe diabetes (< 350 mg/dl). A 2- to 3-fold rise in plasma triglyceride (TG) concentration developed in six week old insulin deficient rats associated with elevated plasma non esterified fatty acid (NEFA) concentrations and decreased very low density lipoprotein secretion. Perfused liver from six week old rats with either moderate or severe diabetes were incapable of increasing hepatic TG secretion when perfusate NEFA concentrations were raised from 0.4 to 1.8 mmol/l. In one year old, spontaneously obese rats, an equivalent degree of hypertriglyceridaemia could be produced with a lesser degree of insulin deficiency, and in this instance very low density lipoprotein secretion was increased over control values. Hepatic TG secretion by perfused livers from these rats with moderate diabetes approximately doubled when perfusate NEFA condentration was raised from 0.40 to 0.85 mmol/l. These results emphasize the complex causality of diabetic hypertriglyeridaemia in situations characterised by comparable degrees of fasting hyperglycaemia.

Age Factors↗

PubMed1997

Molecular mechanisms regulating the myofilament response to Ca2+: implications of mutations causal for familial hypertrophic cardiomyopathy.

In this chapter we consider a current perception of the molecular mechanisms controlling myofilament activation with emphasis on alterations that may occur in familial hypertrophic cardiomyopathy (FHC). FHC is a sarcomeric disease (100) with an autosomal dominant pattern of heritability (27, 51). There is a substantial body of evidence implicating missense mutations in the beta-MHC gene as causal for the development of this disease. Recently, mutations in genes of two thin filament regulatory proteins, cardiac troponin T(cTnT) and alpha-tropomyosin (alpha-Tm), have also been linked to FHC. The commonality among the functional consequences of these mutations remains an important question. This review discusses how these pathological mutations may impact the activation process by disrupting critical structure function relations in both the thick and thin filaments.

Actin Cytoskeleton↗

PubMed1995

Caregivers of Turkish schizophrenic patients: causal attributions, burdens and attitudes to help from the health professionals.

The purpose of this study was to examine the causal attributions, difficulties, perceived and expected help behaviour of health care professionals, and hope for the future well-being of the caregivers of Turkish schizophrenic patients in order to form guidelines for forming a collaboration with the families of schizophrenic patients. Sixty caregivers were interviewed by using a semi-structured interview schedule. The responses of the caregivers were categorized within the guidelines of the literature in this area. The caregivers attributed schizophrenia mainly to psychosocial causes, namely stressful events (50%), family conflicts (40%) and patients' characteristics (28%). The most frequently reported difficulties were family conflicts and disruptions of family life, subjective burden (48%), and financial costs due to the patient (27%). The number of difficulties reported by caregivers was related to the duration of the patient's illness. Caregivers perceived pharmacological treatment (42%), interest and support given to the caregiver (28%), and the hospitalization of the patient (20%) as helpful. THeir expectations of help were in similar areas. About half of the caregivers were optimistic about the future well-being of their relatives. Optimistic and pessimistic caregivers differed in the educational level of the caregiver and the duration of the patient's illness. The results suggested that the families of schizophrenics need support of professionals and the establishment of networks focusing on the caregivers and their relationships with their ill relatives and with health care institutions.

Adult↗

PubMed1991

Correlates of internalizing and externalizing behavior problems: perceived competence, causal attributions, and parental symptoms.

Young adolescents in the clinical range on internalizing, externalizing, and both internalizing and externalizing behavior problems, as well as youth in the normal range on both types of problems, were identified separately using adolescents' self-reports and mothers' reports of behavior problems. In comparisons of groups identified on the basis of either type of informant, differences among the four groups were found in adolescents' self-perceptions of competence and in their fathers' psychological symptoms. Specifically, normals reported a more positive sense of their social acceptance and their behavioral conduct than all clinical groups, and fathers of adolescents in the clinical range on both internalizing and externalizing problems tended to report more psychological symptoms than the fathers of the normal group. Differences were found in mothers' psychological symptoms only when mothers' reports of adolescents' behavior problems were used to identify the groups. No consistent differences among the groups were found on adolescents' causal attributions for success and failure.

Adolescent↗

PubMed1981

Isolating causal effects through experimental changes in parent-child interaction.

A distinction is made between functional and intentional control in parent-child interaction. These concepts are drawn, respectively, from operant and cognitive models of interaction process. Experimental evidence is presented that cognitive factors such as expectations or hypotheses indeed affect the relations between parents and their own children. This necessitates a further distinction between long-term and short-term causal effects: Since changes in parents' expectations for their children may lag behind actual changes in children's behavior, short-term effects inferred from observations of ongoing interactions may not reflect the long-term dynamics of the relationship.

Adult↗

PubMed1981

Parent and child causal attributions related to the child's clinical problem.

Parents and children were asked to give causal attributions related to the child's learning or behavior problems and an area of success. Actor-observer differences and tendencies of actors to make differential attributions for their positive and negative outcomes were examined. A significant number of parents and children were in disagreement regarding the cause of the child's problem. Parents made significantly more internal than external attributions for children's presenting problems. In contrast, children were evenly distributed in problem attributions. Both parents and children made significantly more internal success attributions. Research with clinical child populations is highlighted as a valuable way to validate, expand, and refine attribution theory while clarifying its practical applications.

Adolescent↗

PubMed1996

Connections between reading disability and behavior problems: testing temporal and causal hypotheses.

In this study of children's reading and behavior problem status from Grade 2 to Grade 4 of elementary school, we tested hypotheses concerned with the temporal and causal connections between these two closely associated disorders. Children with both, either, or neither kinds of problems were followed up over 2 years. While reading disability remained stable over time, there was greater variability in behavior problem status. Our data did not support the claim that reading problems lead to the development of behavior problems. Children who were comorbid had the worst outcome at follow-up, suggesting that behavior problems may exacerbate reading delay. Reading-disabled children were lower (albeit in the normal range) on intelligence, but when IQ was controlled, large group differences on reading and spelling were still evident. Attention deficit hyperactivity disorder (ADHD) type behavior problems significantly differentiated children with comorbid problems from children with behavior problems alone. Sex differences were noted in the association, with two-thirds of reading-disabled boys also having behavior problems and two-thirds of reading-disabled girls having no behavior problems, suggesting that pathways to reading disability may be gender specific.

Aggression↗