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PubMed2000

Characterization of human crossover interference.

We present an analysis of crossover interference over the entire human genome, on the basis of genotype data from more than 8,000 polymorphisms in eight CEPH families. Overwhelming evidence was found for strong positive crossover interference, with average strength lying between the levels of interference implied by the Kosambi and Carter-Falconer map functions. Five mathematical models of interference were evaluated: the gamma model and four versions of the count-location model. The gamma model fit the data far better than did any of the other four models. Analysis of intercrossover distances was greatly superior to the analysis of crossover counts, in both demonstrating interference and distinguishing between the five models. In contrast to earlier suggestions, interference was found to continue uninterrupted across the centromeres. No convincing differences in the levels of interference were found between the sexes or among chromosomes; however, we did detect possible individual variation in interference among the eight mothers. Finally, we present an equation that provides the probability of the occurrence of a double crossover between two nonrecombinant, informative polymorphisms.

Centromere↗

PubMed2005

Application of the case-crossover design to reduce unmeasured confounding in studies of condom effectiveness.

This analysis examined how unmeasured confounding affects estimates of the effectiveness of condoms in preventing sexually transmitted infections. Data were analyzed from a prospective cohort study of 1,122 female sexually transmitted disease clinic patients in Alabama (1992-1995), wherein participants were evaluated for sexually transmitted infections at six 1-month intervals. Associations between condom use and incident gonorrhea and chlamydia infection were compared between case-crossover and cohort analyses. In a case-crossover analysis of 228 follow-up visits ending in gonorrhea/chlamydia ("case intervals") and 743 self-matched follow-up visits not ending in gonorrhea/chlamydia ("noncase intervals") (183 women), consistent condom use without breakage or slippage was associated with significantly reduced risk of infection relative to nonuse (adjusted risk odds ratio = 0.49, 95% confidence interval: 0.26, 0.92). Conversely, a cohort analysis of 245 case intervals and 3,896 noncase intervals (919 women) revealed no significant reduction in infection risk from consistent use of condoms (adjusted risk odds ratio = 0.79, 95% confidence interval: 0.53, 1.17). Dose-response relations between the number of unprotected sex acts and infection were stronger in the case-crossover analysis (p for trend = 0.009) than in the cohort analysis (p for trend = 0.18). These findings suggest that epidemiologic studies confounded by unmeasured differences between condom users and nonusers underestimate condom effectiveness against these infections. The case-crossover method provides an additional technique for reducing unmeasured confounding in studies of condom effectiveness.

Adult↗

PubMed1995

Analysis of the CMT1A-REP repeat: mapping crossover breakpoints in CMT1A and HNPP.

The CMT1A-REP repeat sequence flanks a 1.5 megabase pair (Mb) segment of chromosome 17p11.2-12 which is duplicated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A) and deleted in hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A-REP repeat is proposed to mediate misalignment and unequal crossover resulting in reciprocal chromosomal rearrangements in CMT1A and HNPP. We have constructed a physical map of the proximal and distal CMT1A-REP repeats. Cloned fragments from CMT1A-REP repeat regions are used to determine the size of the repeats and assess regions of homology. The crossover breakpoints were mapped in series of 30 unrelated CMT1A patients and 22 unrelated HNPP patients. The CMT1A-REP repeat spans approximately 27 kilobase pairs and appears to be continuous. Locations of restriction enzyme sites are highly conserved for the proximal and distal CMT1A-REP repeats. All crossovers mapped within the CMT1A-REP repeat sequence and heterogeneity for breakpoint location demonstrated. Seventy-seven percent (40 to 52) of CMT1A and HNPP chromosomes contained breakpoints which mapped within a 7.9 kb interval, suggesting the presence of a possible 'hotspot'for recombination in CMT1A-REP. DNA sequence analysis for 4 kb of the interval containing the majority of crossovers revealed over 98% sequence identity between proximal and distal CMT1A-REP repeat sequences. Probes useful for molecular-based diagnosis of CMT1A and HNPP are described.

Charcot-Marie-Tooth Disease↗

PubMed2003

Comparison of time series and case-crossover analyses of air pollution and hospital admission data.

BACKGROUND: Time series analysis is the most commonly used technique for assessing the association between counts of health events over time and exposure to ambient air pollution. Recently, case-crossover analysis has been proposed as an alternative analytical approach. While each technique has its own advantages and disadvantages, there remains considerable uncertainty as to which statistical methodology is preferable for evaluating data of this type. METHODS: The objective of this paper is to evaluate the performance of different variations of these two procedures using computer simulation. Hospital admission data were generated under realistic models with known parameters permitting estimates based on time series and case-crossover analyses to be compared with these known values. RESULTS: While accurate estimates can be achieved with both methods, both methods require some decisions to be made by the researcher during the course of the analysis. With time series analysis, it is necessary to choose the time span in the LOESS smoothing process, or degrees of freedom when using natural cubic splines. For case-crossover studies using either uni- or bi-directional control selection strategies, the choice of time intervals needs to be made. CONCLUSIONS: We prefer the times series approach because the best estimates of risk that can be obtained with time series analysis are more precise than the best estimates based on case-crossover analysis.

Air Pollutants↗

PubMed1995

Control sampling strategies for case-crossover studies: an assessment of relative efficiency.

The case-crossover study design is a method to assess the effect of transient exposures on the risk of onset of acute events. Control information for each case is based on his/her past exposure experience, and a self-matched analysis is conducted. Empiric evaluation of five approaches to the analysis of case-crossover data from a study of heavy physical exertion and acute myocardial infarction onset is shown. The data presented are from the Onset Study, a case-crossover study of the determinants of myocardial infarction onset conducted in 45 centers from August 1989 to October 1992. In model 1, exactly one control period (matched on clock-time) was sampled per case. In models 2-4, up to 25 control periods were sampled, and the effect of clock-time on the baseline hazard of infarction was modeled. In model 5, a census of the person-time experienced by each subject over the year preceding the infarction was sampled. The 95% confidence interval for model 1 was 2.7 times wider, and the relative efficiency, defined as v infinity/vM, where vM represents the asymptotic variance estimate of the estimated log relative risk with M control periods sampled per case, was only about 14% of model 5. In models 2-4, the efficiency increased with the number of control periods, regardless of the modeling assumptions. Even with many control periods sampled, models 2-4 achieved only half the efficiency of model 5. The control sampling strategy in any given case-crossover study should be selected with the trade-offs between precision and potential biases of the estimates in mind.

Adult↗

PubMed1979

Simple reaction time crossover occurs in schizophrenic outpatients.

A crossover pattern similar to that reported for inpatient schizophrenics (e.g., Bellissimo and Steffy 1972) has now been found for outpatients, and its frequency of occurrence in these outpatients is comparable to that reported for hospitalized patients by DeAmicas and Cromwell (1978). The process-reactive construct was unrelated to crossover in the current study, although crossover is found only in process patients in hospitalized samples. The difference in findings may be due to the insensitivity of the particular measure of this concept used here, or to the lack of validity for the construct in samples of chronic patients in the community and in treatment. The present results, together with DeAmicas and Cromwell's (1978) data suggestive of the presence of crossover in nondisturbed first degree relatives of schizophrenics, are consistent with an interpretation of this reaction time phenomenon as a behavioral marker of vulnerability. This hypothesis warrants study in a more extensive series of patients, and from a longitudinal perspective in which behavioral measures and clinical-social functioning variables are tracked across time.

Acoustic Stimulation↗

PubMed2000

Crossover innervation after digital nerve injury: myth or reality?

Several clinical studies promulgate the concept that some degree of crossover innervation occurs after digital nerve injuries are sustained and that the intact digital nerve might even substitute for the loss of nerve function on the injured side. Other studies strongly dispute the existence of this phenomenon. An excellent model for evaluation of crossover innervation is bilateral sharp digital nerve lacerations because there is no confusion of anomalous innervation from an intact contralateral nerve. This model avoids problems seen with replanted digits such as the inherent ischemia, multistructural injury, and the frequent crush component. The author evaluates the role of crossover innervation after digital nerve injury by comparing recovery of sensibility after unilateral and bilateral epineural neurorrhaphies. A retrospective review of 74 sharp unilateral and bilateral epineural digital nerve repairs in 54 patients using microsurgical techniques was performed by measurement of Weber's two-point discrimination (2PD). Fifty-four unilateral digital nerve repairs were performed in 46 patients who ranged in age from 8 to 54 years (mean age, 30.8 years). Concomitant flexor tendon injuries occurred in 50% of patients. Injury to repair was less than 1 day in 14.3% of patients, 2 to 7 days in 34.7%, 8 to 30 days in 40.8%, and 31 to 300 days in 10.2%. Follow-up ranged from 6 to 68 months (average follow-up, 13.8 months). Twenty bilateral digital nerve repairs were performed in 8 patients who ranged in age from 6 to 37 years (mean age, 27.6 years). Concomitant flexor tendon injuries occurred in 80% of patients. Injury to repair was less than 1 day in 10% of patients, 2 to 7 days in 60%, 8 to 30 days in 20%, and 31 to 300 days in 10%. Follow-up ranged from 6 to 77 months (average follow-up, 15.8 months). In this series, 2PD averaged 7.8 mm after unilateral digital nerve repairs compared with 7.1 mm after bilateral nerve repairs. Recovery of sensibility was also stratified into groups according to modified American Society for Surgery of the Hand guidelines: excellent, <6 mm; good, 6 to 10 mm; fair, 11 to 15 mm; and poor, >15 mm or protective sensation. Unilateral digital nerve repairs produced excellent results in 27.8% of patients, good in 46.3%, and fair in 25.9% compared with bilateral nerve repairs with excellent results in 15% of patients, good in 70%, and fair in 15%. There was no significant difference in recovery of sensibility after unilateral and bilateral digital nerve repairs. Crossover innervation did not appear to influence the long-term outcome after digital neurorrhaphy.

Adolescent↗

PubMed2001

Selection bias and confounding in case-crossover analyses of environmental time-series data.

The case-crossover study design is a popular analytic tool for estimating the effects of triggers of acute outcomes by environmental exposures. Although this approach controls for time-invariant confounders by design, it may allow for selection bias and confounding by time-varying factors. We conducted a simulation study of the sensitivity of the symmetric bidirectional case-crossover design to time-varying patterns in exposure and outcome. We identified the effects of selection bias and confounding on symmetric bidirectional case-crossover results and offer strategies to eliminate or reduce these biases. Selection bias results when exposure in the reference periods is not identically representative of exposure in the hazard periods, even when the distribution of exposure is stationary. This bias can be estimated and removed. Selection bias also occurs when the distribution of exposure is nonstationary, but the adjusted symmetric bidirectional case-crossover methodology substantially controls for this. Confounding results from a common temporal pattern in the exposure and the outcome time series, but can also be the result of patterns in exposure and outcome that, although asymptotically uncorrelated, are correlated at finite series lengths. All three biases are reduced by choosing shorter referent-spacing lengths. This effect is illustrated using data on air pollution and daily deaths in Chicago.

Air Pollution↗

PubMed1979

Reaction time crossover in process schizophrenic patients, their relatives, and control subjects.

Of 70 process schizophrenic patients clinically assessed and tested for reaction time, 40 showed reaction time crossover. Of the 40 with crossover, 53 of their first degree relatives were clinically assessed and tested. Five of the relatives, found to have psychotic symptoms, were analyzed separately. Also, 41 control subjects without personal or family history of psychiatric disturbance were clinically assessed and tested. The nondisturbed relatives had reaction time crossover (regular minus irregular) significantly greater than the (expected) negative values of the normal control subjects, but not significantly greater than a zero value within subjects. When disturbed and nondisturbed relatives were combined, greater differences indicative of crossover occurred. On the other hand, the relatives, as expected, did not show the slow mean reaction time characteristic of diagnosed schizophrenic patients.

Adolescent↗

PubMed1981

Magnitude of reaction time crossover in process schizophrenic patients in relation to their first-degree relatives.

The reaction time crossover (redundancy associated deficity) scores of 28 process schizophrenics, selected for the presence of crossover, were correlated with the crossover scores of 53 of their first-degree relatives (one to five relatives for each patient.). The resulting product-moment correlation coefficient was .27 (p < .05), thus lending support to the notion of a familial factor in reaction time crossover.

Family↗

PubMed1993

Reaction time crossover in schizotypal subjects.

The present study investigated the relationship between reaction time crossover and schizotypy as measured by Chapman's Physical Anhedonia Scale (PAS). Twenty PAS-identified schizotypal college students and 20 nonschizotypal students were administered a computerized version of Rodnick and Shakow's crossover reaction time task. The hypothesized interaction (crossover) between preparatory interval duration and preparatory interval presentation pattern was observed for PAS-identified schizotypics. Results indicated that subjects identified on the basis of the PAS evidenced reaction time crossover patterns similar to those observed in schizophrenic and at-risk populations.

Acoustic Stimulation↗

PubMed2004

Differential misclassification of exposure in case-crossover studies.

The aim of this study is to examine 2 types of differential misclassification of exposure in case-crossover studies. The first is the outcome-dependent misclassification of exposure, meaning that if an event has occurred, it could affect the reporting of exposure. The second is differential misclassification of exposure as a result of fading memory over time, which arises if the length of the recall period for case and control windows differs. We use empirical data from a case-crossover study of triggers of attacks in Ménière's disease. The study applied the matched-pair interval control window sampling approach. We examined misclassification in relation to 2 different types of exposures: emotional stress and salty food intake. The study covered repeated events reported by the same patients and involved the sampling of many control windows. Because some of these windows were related to case events and some unrelated, we were able to conduct both case-crossover and control-crossover analyses. Although this group of Ménière patients are well aware of their disease, and many of them have definite ideas regarding what triggers attacks, neither outcome-dependent misclassification nor differential misclassification of exposure resulting from fading memory over time seemed to be a major problem.

Cross-Over Studies↗

PubMed2004

Starting a crossover kidney transplantation program in the Netherlands: ethical and psychological considerations.

On April 15th, 2003, the first crossover kidney transplantation took place in The Netherlands. In September of the same year, a national database was established to facilitate kidney exchange between two donor-recipient couples. During 2004, kidneys from living donors will be exchanged between the seven university medical centers in The Netherlands. One of the conditions for successfully implementing this program was the need to address the ethical and psychologic implications involved. In this article we will discuss the ethical and psychologic considerations that are accompanying the practical preparations for the first Dutch crossover transplantation program. We identified five topics of interest: the influence of "donation by strangers" on the motivation and willingness of donor-patient couples, the issue of anonymity, the loss of the possibility of "medical excuses" for unwilling donors, the view that crossover is a first step to commercial organ trade, and the interference with existing organ donation programs. We concluded that whether viewed separately or in combination, these issues do not impede the efficient organization of a crossover program or raise worrying ethical issues.

Anonyms and Pseudonyms↗

PubMed1997

Tam1, a telomere-associated meiotic protein, functions in chromosome synapsis and crossover interference.

The TAM1 gene of Saccharomyces cerevisiae is expressed specifically during meiosis and encodes a protein that localizes to the ends of meiotic chromosomes. In a tam1 null mutant, there is an increase in the frequency of chromosomes that fail to recombine and an associated increase in homolog nondisjunction at meiosis I. The tam1 mutant also displays an increased frequency of precocious separation of sister chromatids and a reduced efficiency of distributive disjunction. The defect in distributive disjunction may be attributable to overloading of the distributive system by the increased number of nonrecombinant chromosomes. Recombination is not impaired in the tam1 mutant, but crossover interference is reduced substantially. In addition, chromosome synapsis is delayed in tam1 strains. The combination of a defect in synapsis and a reduction in interference is consistent with previous studies suggesting a role for the synaptonemal complex in regulating crossover distribution. tam1 is the only known yeast mutant in which the control of crossover distribution is impaired, but the frequency of crossing over is unaffected. We discuss here possibilities for how a telomere-associated protein might function in chromosome synapsis and crossover interference.

Chromosome Mapping↗

PubMed2004

Crossover from capillary fingering to viscous fingering for immiscible unstable flow:Experiment and modeling.

Invasion percolation with trapping (IPT) and diffusion-limited aggregation (DLA) are simple fractal models, which are known to describe two-phase flow in porous media at well defined, but unphysical limits of the fluid properties and flow conditions. A decade ago, Fernandez, Rangel, and Rivero predicted a crossover from IPT (capillary fingering) to DLA (viscous fingering) for the injection of a zero-viscosity fluid as the injection velocity was increased from zero. [Phys. Rev. Lett. 67, 2958 (1991)]]. We have performed experiments in which air is injected into a glass micromodel to displace water. These experiments clearly demonstrate this crossover as the injection velocity of the air is increased. Furthermore, simulations, using our standard pore-level model, also support the predicted IPT-to-DLA crossover, as well as the predicted power-law behavior of the characteristic crossover length.

Journal Article↗

PubMed2006

Scaling in the crossover from random to correlated growth.

In systems where deposition rates are high compared to diffusion, desorption, and other mechanisms that generate correlations, a crossover from random to correlated growth of surface roughness is expected at a characteristic time t0. This crossover is analyzed in lattice models via scaling arguments, with support from simulation results presented here and in other works. We argue that the amplitudes of the saturation roughness and of the saturation time t(x) scale as t0(1/2) and t0, respectively. For models with lateral aggregation, which typically are in the Kardar-Parisi-Zhang (KPZ) class, we show that t0 approximately p(-1), where p is the probability of the correlated aggregation mechanism to take place. However, t0 approximately p(-2) is obtained in solid-on-solid models with single-particle deposition attempts. This group includes models in various universality classes, with numerical examples being provided in the Edwards-Wilkinson (EW), KPZ, and Villain-Lai-Das Sarma (nonlinear molecular-beam epitaxy) classes. Most applications are for two-component models in which random deposition, with probability 1-p, competes with a correlated aggregation process with probability p. However, our approach can be extended to other systems with the same crossover, such as the generalized restricted solid-on-solid model with maximum height difference S, for large S. Moreover, the scaling approach applies to all dimensions. In the particular case of one-dimensional KPZ processes with this crossover, we show that t0 approximately nu(-1) and nu approximately lambda(2/3), where nu and lambda are the coefficients of the linear and nonlinear terms of the associated KPZ equations. The applicability of previous results to models in the EW and KPZ classes is discussed.

Journal Article↗

PubMed2006

Crossover from the pair contact process with diffusion to directed percolation.

Crossover behaviors from the pair contact process with diffusion (PCPD) and the driven PCPD (DPCPD) to the directed percolation (DP) are studied in one dimension by introducing a single particle annihilation and/or branching dynamics. The crossover exponents phi are estimated numerically as 1/phi approximately 0.58 +/- 0.03 for the PCPD and 1/phi approximately 0.49+/-0.02 for the DPCPD. Nontriviality of the PCPD crossover exponent strongly supports the non-DP nature of the PCPD critical scaling, which is further evidenced by the anomalous critical amplitude scaling near the PCPD point. In addition, we find that the DPCPD crossover is consistent with the mean field prediction of the tricritical DP class as expected.

Journal Article↗

PubMed2006

Crossover behavior in failure avalanches.

Composite materials, with statistically distributed thresholds for breakdown of individual elements, are considered. During the failure process of such materials under external stress (load or voltage), avalanches consisting of simultaneous rupture of several elements occur, with a distribution D(Delta) of the magnitude Delta of such avalanches. The distribution is typically a power law D(Delta) proportional to Delta (-xi). For the systems we study here, a crossover behavior is seen between two power laws, with a small exponent xi in the vicinity of complete breakdown and a larger exponent xi for failures away from the breakdown point. We demonstrate this analytically for bundles of many fibers where the load is uniformly distributed among the surviving fibers. In this case xi=3/2 near the breakdown point and xi=5/2 away from it. The latter is known to be the generic behavior. This crossover is a signal of imminent catastrophic failure of the material. Near the breakdown point, avalanche statistics show nontrivial finite size scaling. We observe similar crossover behavior in a network of electric fuses, and find xi=2 near the catastrophic failure and xi=3 away from it. For this fuse model power dissipation avalanches show a similar crossover near breakdown.

Journal Article↗