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PubMed2006

Measuring diffusion of molecules into individual polymer particles by confocal Raman microscopy.

Raman microscopy is a powerful method for providing spatially resolved, chemically selective information about the composition of materials. With confocal collection optics, the method is well suited to the analysis of small particles in contact with liquid solutions. In this work, the transport of an organic solvent component into small polystyrene particles is investigated. An inverted confocal Raman microscope is used to acquire spectra from individual 75-microm polystyrene particles in contact with acetonitrile/water mixtures. Monitoring the Raman scattering from the C[triple bond]N stretching mode of acetonitrile provides a measure of solvent uptake into the polymer material. The small collection volume defined by the confocal optics provides the micrometer spatial resolution needed to track solvent concentration at different locations within the particle with 30-s time resolution. The volume fraction of acetonitrile in water in the surrounding solution was varied in order to determine the concentration dependence of the diffusion kinetics. Modeling the transport of molecules into a particle was addressed by using finite element methods for the evaluation of the coupled space- and time-dependent differential equations that govern the molecular transport. The results indicate that the diffusion coefficient changes with the local solvent concentration in the polymer. At longer times, with the highest acetonitrile concentrations, an evolution of the solvent transport mechanism was observed, from a diffusive rate that depends on local concentration to a linear increase in concentration with time accompanied by measurable swelling of the particle volume.

Journal Article↗
PubMed2004

Carbonyl carbon transverse relaxation dispersion measurements and ms-micros timescale motion in a protein hydrogen bond network.

A constant-time, Carr-Purcell-Meiboom-Gill (CPMG) transverse relaxation, R(2), dispersion experiment for carbonyl carbons was designed and executed to detect micros-ms time-scale dynamics of protein backbone carbonyl sites. Because of the large (ca. 55 Hz) C(alpha)-C' J-coupling, the carbonyl signal intensity is strongly modulated as the spacing between CPMG pulses is varied, in uniformly (13)C enriched proteins, unless care is taken to minimize the perturbation of the C(alpha) magnetization by the CPMG pulses. CPMG pulse trains consisting of either a band-selective pulse, such as RE-BURP, or rectangular (with an excitation null in the C(alpha) region of the spectrum) pulses were employed in order to minimize C' signal modulation by C(alpha)-C' J-coupling. The performance of these types of CPMG refocusing pulses was assessed by computer simulation, and by comparing dispersion profiles measured for (1) uniformly [(13)C,(15)N, (2)H] ((2)H at non-labile hydrogen sites) labeled, and (2) uniformly (15)N/selectively-(13)C' labeled samples of HIV-1 protease bound to a potent inhibitor, DMP323. In addition, because the uniformly (13)C/(15)N/(2)H labeled sample was well suited to measure (15)N and (1)H R(2) dispersion as well as (13)C' dispersion, conformational exchange in the inter subunit beta-sheet hydrogen-bond network of the inhibitor-bound protease was elucidated using relaxation dispersion data of all three types of nuclei.

Carbon↗
PubMed2006

Robustness of surrogates of biodiversity in marine benthic communities.

The usefulness of surrogates to estimate complex variables describing community structure, such as the various components of biodiversity, is long established. Most attention has been given to surrogates of species richness and species diversity and has focused on identifying a subset of taxa as a surrogate of total community richness or diversity. In adopting a surrogate measure, it is assumed that the relationship between the surrogate(s) and total richness or diversity is consistent in both space and time. These assumptions are rarely examined explicitly. We examined the robustness of potential surrogates of familial richness and multivariate community structure for macrofauna communities inhabiting artificial kelp holdfasts by comparing among communities of dissimilar ages and among communities established at different times of the year. This is important because most benthic "landscapes" will be a mosaic of patches reflecting different intensities, frequencies, and timing of disturbances. The total abundance of organisms and familial richness of crustaceans or polychaetes were all good predictors of total familial richness (R2 > 0.68). In contrast, while the familial richness of other groups, such as mollusks and echinoderms, were well correlated with total familial richness for communities at an early stage of development, the strength of these relationships declined with community age. For multivariate community structure, carefully selected subsets of approximately 10% of the total taxa yielded similar patterns to the total suite of taxa, irrespective of the age of the community. Thus, useful surrogates of both familial richness and multivariate community structure can be identified for this type of community. However, the choice of technique for selecting surrogate taxa largely depends on the nature of the pilot data available, and careful selection is required to ensure that surrogates perform consistently across different-aged communities. While the specific taxa selected as surrogates will vary among different communities, and possibly even among similar communities at different sites, the techniques and the concepts we address are applicable to any community type.

Animals↗
PubMed2003

Distinct geographic patterns of genetic diversity are maintained in wild barley (Hordeum vulgare ssp. spontaneum) despite migration.

Mutations arise in a single individual and at a single point in time and space. The geographic distribution of mutations reflects both historical population size and frequency of migration. We employ coalescence-based methods to coestimate effective population size, frequency of migration, and level of recombination compatible with observed genealogical relationships in sequence data from nine nuclear genes in wild barley (Hordeum vulgare ssp. spontaneum), a highly self-fertilizing grass species. In self-fertilizing plants, gamete dispersal is severely limited; dissemination occurs primarily through seed dispersal. Also, heterozygosity is greatly reduced, which renders recombination less effective at randomizing genetic variation and causes larger portions of the genome to trace a similar history. Despite these predicted effects of this mating system, the majority of loci show evidence of recombination. Levels of nucleotide variation and the patterns of geographic distribution of mutations in wild barley are highly heterogeneous across loci. Two of the nine sampled loci maintain highly diverged, geographic region-specific suites of mutations. Two additional loci include region-specific haplotypes with a much shallower coalescence. Despite inbreeding, sessile growth habit, and the observation of geographic structure at almost half of sampled loci, parametric estimates of migration suggest that seed dispersal is sufficient for migration across the approximately 3,500-km range of the species. Recurrent migration is also evident based on the geographic distribution of mutational variation at some loci. At one locus a single haplotype has spread rapidly enough to occur, unmodified by mutation, across the range of the species.

Biological Evolution↗
PubMed2006

Sensitivity of CFP/YFP and GFP/mCherry pairs to donor photobleaching on FRET determination by fluorescence lifetime imaging microscopy in living cells.

Fluorescent protein-based FRET is a powerful method for visualizing protein-protein interactions and biochemical reactions in living cells. It can be difficult, however, to avoid photobleaching when observing fluorescent cells under the microscope, especially those expressing CFP. We compared the sensitivity of two protein-based FRET pairs to light-induced fluorescence changes in the donor, on FRET determination by fluorescence lifetime imaging microscopy (FLIM). Thanks to the very low excitation light levels of the time- and space-correlated single photon counting (TSCSPC) method, FLIM acquisitions were achieved without donor photobleaching. Here, we show that photobleaching of CFP by a mercury lamp under the microscope induced a decrease in the mean fluorescence lifetime, which interfered with FRET determination between CFP and YFP. Importantly, the range of light-induced variation of the mean fluorescence lifetime of CFP was not proportional to the decrease in the steady state fluorescence intensity and varied from cell to cell. The choice of the CFP/YFP pair therefore requires that the cells be observed and analyzed at very low light levels during the whole FRET experiment. In contrast, the GFP/mCherry pair provided an accurate FRET measurement by FLIM, even if some GFP photobleaching took place. We thus demonstrate that CFP can be an unreliable donor for FRET determination in living cells, due to its photosensitivity properties. We demonstrate that the GFP/mCherry pair is better suited for FRET measurement by FLIM in living cells than the CFP/YFP pair.

Bacterial Proteins↗
PubMed2002

A novel instrument for the evaluation of the pleural space: an experience in 34 patients.

STUDY OBJECTIVES: To test a novel semirigid pleuroscope to be used by pulmonologists for the diagnosis and treatment of pleural diseases. DESIGN: Prospective study. SETTING: Three tertiary referral centers for pulmonary diseases. PATIENTS: Thirty-four patients who were referred for medical thoracoscopy between September 2000 and April 2001. MEASUREMENTS AND RESULTS: Thirty-six procedures were performed. The most common indications were for pleurodesis of a malignant pleural effusion (53%) or for evaluation of an exudative effusion of unknown etiology (44%). All operators found the instrument easy to use. In all but one case, the images were thought to be adequate, despite the presence of adhesions in 12 patients and loculations in 8 patients. Pleural biopsies were performed in 13 patients, and talc pleurodesis procedures were performed in 25 patients. Mean (+/- SD) duration of chest tube drainage was 2.9 +/- 1.8 days postprocedure. There were no complications. CONCLUSIONS: The prototype semirigid pleuroscope is a useful instrument in the diagnosis and management of pleural diseases. It is similar in design to a standard flexible bronchoscope, so the skills involved in operating the instrument should already be familiar to the practicing pulmonologist. It is compatible with existing video processors and light sources, so little additional equipment must be added to the endoscopy suite. The semirigid pleuroscope may allow for an increase in the performance of medical thoracoscopy by pulmonologists.

Equipment Design↗
PubMed2001

Extrapericardial cardiac tamponade caused by traumatic retrosternal hematoma.

Cardiac tamponade is an uncommon complication of blunt chest trauma, resulting typically from hemorrhage into the pericardial space. We report a case of hemodynamic compromise secondary to an extrapericardial compression caused by the acute formation of a retrosternal hematoma associated with a sternal fracture. The patient was involved in a violent deceleration accident. Initially, he only complained of an anterior thoracic pain, but subsequently became restless, pale, and dyspneic. A severe hypotension associated with sinus bradycardia (45 bpm) rapidly occurred. Both jugular veins became markedly turgescent, but no significant pulsus paradoxus was noted. Echocardiography disclosed a large hematoma, compressing anteriorly both the right ventricular cavity and outflow tract. Surgical evacuation of the retrosternal hematoma related to a bifocal fracture of the manubrium was followed by instantaneous hemodynamic improvement. Regional extrapericardial tamponade secondary to the acute formation of compressive retrosternal hematoma is an unusual cause of circulatory failure after severe blunt chest trauma. Since conventional clinical signs associated with typical tamponade physiology may be lacking in this setting, echocardiography is ideally suited for early recognition of this unusual condition.

Accidents, Traffic↗
PubMed1998

Doxorubicin distribution in multicellular prostate cancer spheroids evaluated by confocal laser scanning microscopy and the "optical probe technique".

Multicell-mediated drug resistance is a major impediment for the effectiveness of chemotherapeutic approaches and has been shown to be a feature of many solid tumors. We used confocal laser scanning microscopy to evaluate the depth distribution of the fluorescent cytostatic drug doxorubicin (Dox) in two size classes of multicellular cancer spheroids (MCS) (psi150+/-50 microm and 350+/-50 microm). MCS (psi150+/-50 microm) solely consist of proliferating cells, whereas in MCS (psi350+/-50 microm) peripheral proliferating cell layers are followed in the depth of the tissue by drug resistant quiescent cell areas. A technique was developed which allows noninvasively to trace fluorescence distributions down to a depth of approximately 180 microm in living MCS. This was achieved by confocal radial recordings of the mean Dox fluorescence in 600 microm2 regions of interest (ROI), equidistantly spaced (10 microm) from the center of MCS towards their periphery. The resulting fluorescence intensity profiles were subsequently corrected for absorbtion and light scattering in the depth of the tissue by a convenient algorithm. A 10 min incubation of MCS (psi150+/-50 microm) with Dox (10 microM) led to a peripheral accumulation, after 2 h Dox was homogeneously distributed within the whole MCS. In contrast, after Dox treatment of MCS (psi350+/-50 microm) for 2 h, the drug was accumulated within the peripheral proliferating cell rim of 78+/-8 microm, whereas deeper, quiescent cell layers remained unstained. When MCS were incubated with verapamil, cyclosporin A, orthovanadate, and quinidine, which are known to reverse P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), Dox accumulated also in deeper cell layers. Genistein and indometacin which reverse multidrug resistance mediated by the multidrug resistance-associated protein (MRP) were without effects. The optical probe technique proved to be well suited to study MDR in a living three dimensional tissue context.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Hepatic MR imaging: comparison of RARE derived sequences with conventional sequences for detection and characterization of focal liver lesions.

BACKGROUND: We compared two T2-weighted turbo spin echo (TSE) sequences with a T2-weighted conventional SE (CSE) sequence to determine whether sequences derived from rapid acquisition with relaxation enhancement such as TSE could replace CSE for the detection and subsequent characterization of focal liver lesions. METHODS: A total of 55 consecutive patients with 107 liver lesions underwent magnetic resonance imaging examinations at 1.5 Tesla, with a constant imaging protocol. TSE pulse sequences were acquired with eight echo trains (repetition time [TR], 4718 ms; echo time [TE], 90 ms; acquisition time [TA], 4.03 min; and a symmetric k-space ordering scheme) and 11 echo trains (TR, 4200 ms; TE, 140 ms; TA, 4.40 min; and an asymmetric k-space ordering scheme) and compared with CSE (TR, 2300 ms; TE, 45/90 ms; TA, 9.53 min). Images were analyzed qualitatively by scoring image quality and artifacts and counting focal liver lesions by independent reading with consensus obtained for discrepancies. Quantitative analysis was performed by measuring signal-to-noise (S/N), contrast-to-noise (C/N), and tumor-liver signal intensity (T/L) ratios. RESULTS: T2-weighted TSE sequences provided better subjective image quality and reduced artifacts as compared with the T2-weighted CSE sequence. CSE and TSE sequences exhibited no statistically significant differences in liver S/N, lesion-liver C/N (CSE TE, 90 ms: 18.6 +/- 14.0; TSE TE, 90 ms: 16.5 +/- 12.9) and the detectability of focal liver lesions. Heavily T2-weighted TSE with a TE of 140 ms allowed correct characterization of focal liver lesions based on a T/L ratio of 3.0 in 84% of patients. CONCLUSIONS: T2-weighted TSE sequences are as suited as CSE for the detection (TE, 90 ms), and appear to be superior for the characterization (TE, 140 ms), of focal hepatic lesions. Whether a single sequence, such as a double-echo TSE or a single-echo TSE sequence with a TE between 110 and 120 ms, might perform both functions as well or better than CSE is unknown. However, because of time savings, TSE eventually may be preferred over CSE.

Artifacts↗
PubMed2003

QTL fine-mapping with recombinant-inbred heterogeneous stocks and in vitro heterogeneous stocks.

We compared strategies to fine-map Quantitative Trait Loci (QTL) in mice with heterogeneous stocks (HS). We showed that a panel of about 100 Recombinant Inbred Lines (RIL) derived from an HS, and which we called an RIHS, was ideally suited to fine-map QTL to very high resolution, without the cost of additional genotyping. We also investigated a strategy based on in vitro fertilization of large numbers of F(1) offspring of HS males crossed with an inbred line (IVHS). This method required some additional genotyping but avoided the breeding delays and costs associated with the construction of an RI panel. We showed that QTL detection was higher by using RIHS than with IVHS and that it was independent of the number of RI lines, provided the total number of animals phenotyped was constant. However, fine-mapping accuracy was slightly better with IVHS. We also investigated the effects of varying the number of HS generations and using multiallelic microsatellites instead of SNPs. We found that quite modest generation times of 10-20 generations were optimal. Microsatellites were superior to SNPs only when the generation time was 30 or more and when the markers were widely spaced.

Analysis of Variance↗
PubMed2002

The Gray Lecture 2001: coming technical advances in radiation oncology.

PURPOSE: To review the current limits on the efficacy of radiotherapy (RT) due to technical factors and to assess the potential for major improvements in technology. METHODS AND MATERIALS: The method of this review was to assess the efficacy of current RT in general terms; strategies for improving RT; historical record of technological advances; rationale for further reductions of treatment volume; and importance of defining and excluding nontarget tissues from the target volume. The basis for the interest in proton beam RT is developed, and the relative dose distributions of intensity-modulated radiotherapy (IMRT) and intensity-modulated proton RT (IMPT) are discussed. The discovery of the proton and the first proposal that protons be used in RT is described. This is followed by a brief mention of the clinical outcome studies of proton RT. Likely technical advances to be integrated into advanced proton RT are considered, specifically, four-dimensional treatment planning and delivery. Finally, the increment in cost of some of these developments is presented. RESULTS: For definitive RT, dose limits are set by the tolerance of normal tissues/structures adjacent or near to the target. Using imaging fusion of CT, MRI, positron emission tomography, magnetic resonance spectroscopic imaging, and other studies will result in improved definition of the target margins. Proton beams are likely to replace photon beams because of their physical characteristics. Namely, for each beam path, the dose deep to the target is zero, across the target it is uniform, and proximal to the target it is less. Proton therapy can use as many beams, beam angles, noncoplanar, and dynamic, as well as static, intensity modulation, as can photon plans. The ability for much greater accuracy in defining the target position in space and then maintaining the target in a constant position in the radiation beam despite target movement between and during dose fractions will be possible. The cost of proton RT will be modestly higher than comparable high technology photon therapy. CONCLUSION: The technology of RT is clearly experiencing intense and rapid technical developments as pertains to treatment planning and dose delivery. It is predicted that radical dose RT will move to proton beam technology and that the treatment will be four dimensional (the fourth dimension is time). The impact will be higher tumor control probability and reduced frequency and severity of treatment-related morbidity.

Humans↗
PubMed2005

[Coming technical advances in radiation oncology].

PURPOSE: To review the current limits on the efficacy of radiotherapy (RT) due to technical factors and to assess the potential for major improvements in technology. METHODS AND MATERIALS: The method of this review was to assess the efficacy of current RT in general terms; strategies for improving RT; historical record of technological advances; rationale for further reductions of treatment volume; and importance of defining and excluding nontarget tissues from the target volume. The basis for the interest in proton beam RT is developed, and the relative dose distributions of intensity-modulated radiotherapy (IMRT) and intensity-modulated proton RT (IMPT) are discussed. The discovery of the proton and the first proposal that protons be used in RT is described. This is followed by a brief mention of the clinical outcome studies of proton RT. Likely technical advances to be integrated into advanced proton RT are considered, specifically, four-dimensional treatment planning and delivery. Finally, the increment in cost of some of these developments is presented. RESULTS: For definitive RT, dose limits are set by the tolerance of normal tissues/structures adjacent or near to the target. Using imaging fusion of CT, MRI, positron emission tomography, magnetic resonance spectroscopic imaging, and other studies will result in improved definition of the target margins. Proton beams are likely to replace photon beams because of their physical characteristics. Namely, for each beam path, the dose deep to the target is zero, across the target it is uniform, and proximal to the target it is less. Proton therapy can use as many beams, beam angles, noncoplanar, and dynamic, as well as static, intensity modulation, as can photon plans. The ability for much greater accuracy in defining the target position in space and then maintaining the target in a constant position in the radiation beam despite target movement between and during dose fractions will be possible. The cost of proton RT will be modestly higher than comparable high technology photon therapy. CONCLUSION: The technology of RT is clearly experiencing intense and rapid technical developments as pertains to treatment planning and dose delivery. It is predicted that radical dose RT will move to proton beam technology and that the treatment will be four dimensional (the fourth dimension is time). The impact will be higher tumor control probability and reduced frequency and severity of treatment-related morbidity.

Humans↗
PubMed1994

Electrophysiological properties of substantia gelatinosa neurones in a novel adult spinal slice preparation.

A novel longitudinal spinal cord slice prepared from adult rats aged 3-6 weeks is described. This preparation differs from conventional slices in that it retains multiple dorsal roots, each more than 10 mm in length, and presents a sagittal section through the laminae of the dorsal and ventral horns. The substantia gelatinosa can be visually distinguished from the other laminae of the dorsal horn, thus making the preparation particularly suited for the study of neurones located in this region. Extracellular recordings were made from 142 substantia gelatinosa cells, most of which responded to electrical stimulation of a dorsal root. Using measurements of latency it was possible to estimate conduction velocities for afferent input fibres. The effects of iontophoretically applied excitatory amino acids and of tachykinin peptides on spontaneous and afferent-evoked firing are briefly described. The preparation has applications in the investigation of mechanisms of primary afferent transmission within the dorsal horn and of transmission of afferent input between successive spinal segments.

Animals↗
PubMed1992

Confocal microscopy in microgravity research.

We have studied the application and the feasibility of confocal scanning laser microscopy (CSLM) in microgravity research. Its superior spatial resolution and 3D imaging capabilities and its use of light as a probe, render this instrument ideally suited for the study of living biological material on a (sub-)cellular level. In this paper a number of pertinent biological microgravity experiments is listed, concentrating on the direct observation of developing cells and cellular structures under microgravity condition. A conceptual instrument design is also presented, aimed at sounding rocket application followed by Biorack/Biolab application at a later stage.

Animals↗
PubMed1981

Mannitol.

Mannitol is an osmotic diuretic with properties that suit it to a variety of clinical situations. Despite the paucity of controlled studies that precisely define optimal use, a consensus based on published work and clinical experience may be reached. Mannitol can be used prophylactically, as a diagnostic aid, or as therapy for the oliguric state. The diuretic properties of mannitol are also useful in patients with refractory edema or intoxications by aspirin, barbiturates, or bromide. As an extracellular solute, the drug may ameliorate intracranial hypertension or symptoms of dialysis dysequilibrium. The renal and systemic effects of this versatile agent are discussed.

Acute Kidney Injury↗
PubMed2003

[Biochemical analysis of epidermal lipids].

According to the knowledge acquired some 15 years ago, the cutaneous lipids may be classified into 2 families: the "neutral" lipids, represented by cholesterol, cholesterol esters, cholesterol sulphate, triglycerides, free fatty acids, squalen and alcanes, and the "polar" lipids including phospholipids (phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingomyeline) and sphingolipids (ceramides I-VII, monohexosylceramides). From the functional point of view, free fatty acids, cholesterol, and ceramides organised in layers are the most important components of intercellular spaces of the stratum corneum. Analytic methods have been recently developed to help understand the structural organisation of these various molecules within the horny layer and their influence on the epidermal barrier function. Raman microspectroscopy or X-ray diffraction are most frequently used. Differential calorimetry and fluorescence or infrared spectroscopy provide complementary information. The principal findings are: lamellar structure depends on the presence of ceramides supplemented by adequate quantities of free fatty acids and cholesterol; ceramide chains interact to provide the ordered structure and ceramide-1 is necessary for stabilisation of lipid layers; cholesterol may regulate the molecular mobility of hydrocarbon chains within the bi-layers. Knowledge of the molecular structure of the barrier lipids finds several applications, e.g.: in pharmacology--conception of new formulations adapted for percutaneous and topical application of drugs; in dermatology--comprehension of physiopathologic mechanisms of various dermatoses; in biotechnology--development of skin substitutes with valid stratum corneum barrier; in cosmetics--choice of best formulations suited for reconstruction of the intercellular lipid substance.

Ceramides↗
PubMed1997

Opercular jetting during fast-starts by flatfishes

When attacked by predators, flatfishes perform fast-starts that result in a rapid take-off from the ocean bottom on which they lie. High-speed video recordings of the blind side of flatfishes indicate that they expel a coherent jet of water from the blind-side opercular valve during take-off. Buccal pressure recordings in winter flounder (Pseudopleuronectes americanus) show that a buccal pressure pulse begins 0­20 ms before the beginning of the fast-start and has a range of mean magnitudes for three individuals of 1.6­10.7 kPa. We hypothesize that one function of the opercular jet in flatfishes may be to reduce the effects of Stefan adhesion. Stefan adhesion occurs as the fish lifts its head up rapidly from the ocean bottom, when water must flow into the space forming beneath the fish. Water viscosity opposes this rapid shear, and a suction pressure develops under the fish, making it more difficult for the fish to escape from the bottom. To estimate the magnitude of Stefan adhesion, we simulated fast-starts using a physical model in which a dead flounder was pulled upwards with an acceleration of 95 m s-2. Results from the physical model indicate that up to 35 % of the total force required to lift the head at 20 ms into the start can be attributed to Stefan adhesion. Despite this large adhesion force, previous work has shown that live flatfish do not show improved fast-start performance when Stefan adhesion has been eliminated by starting the fish from an open wire grid. Thus, live fishes are likely to be using behavioral mechanisms to reduce the adhesion force. Both the timing and location along the body of the opercular jet indicate that it is ideally suited to attenuate the effects of Stefan adhesion. Propping the body up on the median fins may also reduce adhesion by increasing the initial distance between the fish and the ocean floor.

Journal Article↗
PubMed2000

Linkage analysis in the presence of errors IV: joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified.

There is a lot of confusion in the literature about the "differences" between "model-based" and "model-free" methods and about which approach is better suited for detection of the genes predisposing to complex multifactorial phenotypes. By starting from first principles, we demonstrate that the differences between the two approaches have more to do with study design than statistical analysis. When simple data structures are repeatedly ascertained, no assumptions about the genotype-phenotype relationship need to be made for the analysis to be powerful, since simple data structures admit only a small number of df. When more complicated and/or heterogeneous data structures are ascertained, however, the number of df in the underlying probability model is too large to have a powerful, truly "model-free" test. So-called "model-free" methods typically simplify the underlying probability model by implicitly assuming that, in some sense, all meioses connecting two affected individuals are informative for linkage with identical probability and that the affected individuals in a pedigree share as many disease-predisposing alleles as possible. By contrast, "model-based" methods add structure to the underlying parameter space by making assumptions about the genotype-phenotype relationship, making it possible to probabilistically assign disease-locus genotypes to all individuals in the data set on the basis of the observed phenotypes. In this study, we demonstrate the equivalence of these two approaches in a variety of situations and exploit this equivalence to develop more powerful and efficient likelihood-based analogues of "model-free" tests of linkage and/or linkage disequilibrium. Through the use of a "pseudomarker" locus to structure the space of observations, sib-pairs, triads, and singletons can be analyzed jointly, which will lead to tests that are more well-behaved, efficient, and powerful than traditional "model-free" tests such as the affected sib-pair, transmission/disequilibrium, haplotype relative risk, and case-control tests. Also described is an extension of this approach to large pedigrees, which, in practice, is equivalent to affected relative-pair analysis. The proposed methods are equally applicable to two-point and multipoint analysis (using complex-valued recombination fractions).

Case-Control Studies↗