Linkage Tests Research Articles

Genetic architecture reconciles linkage and association studies of complex traits.

Linkage studies have successfully mapped loci underlying monogenic disorders, but mostly failed when applied to common diseases. Conversely, genome-wide association studies (GWASs) have identified replicable associations between thousands of SNPs and complex traits, yet capture less than half of the total heritability. In the present study we reconcile these two approaches by showing that linkage signals of height and body mass index (BMI) from 119,000 sibling pairs colocalize with GWAS-identified loci. Concordant with polygenicity, we observed the following: a genome-wide inflation of linkage test statistics; that GWAS results predict linkage signals; and that adjusting phenotypes for polygenic scores reduces linkage signals. Finally, we developed a method using recombination rate-stratified, identity-by-descent sharing between siblings to unbiasedly estimate heritability of height (0.76 ± 0.05) and BMI (0.55 ± 0.07). Our results imply that substantial heritability remains unaccounted for by GWAS-identified loci and this residual genetic variation is polygenic and enriched near these loci.

Nodule-specific cysteine-rich peptide 343 is required for symbiotic nitrogen fixation in Medicago truncatula.

Symbiotic interactions between legumes and rhizobia lead to the development of root nodules and nitrogen fixation by differentiated bacteroids within nodules. Differentiation of the endosymbionts is reversible or terminal, determined by plant effectors. In inverted repeat lacking clade legumes, nodule-specific cysteine-rich (NCR) peptides control the terminal differentiation of bacteroids. Medicago truncatula contains ∼700 NCR-coding genes. However, the role of few NCR peptides has been demonstrated. Here, we report characterization of fast neutron 2106 (FN2106), a symbiotic nitrogen fixation defective (fix-) mutant of M. truncatula. Using a transcript-based approach, together with linkage and complementation tests, we showed that loss-of-function of NCR343 results in impaired bacteroid differentiation and/or maintenance and premature nodule senescence of the FN2106 mutant. NCR343 was specifically expressed in nodules. Subcellular localization studies showed that the functional NCR343-YFP fusion protein colocalizes with bacteroids in symbiosomes in infected nodule cells. Transcriptomic analyses identified senescence-, but not defense-related genes, as being significantly upregulated in ncr343 (FN2106) nodules. Taken together, results from our phenotypic and transcriptomic analyses of a loss-of-function ncr343 mutant demonstrate an essential role of NCR343 in bacteroid differentiation and/or maintenance required for symbiotic nitrogen fixation.

Sensitivity and specificity of two investigational Point of care tests for Syphilis and HIV (PoSH Study) for the diagnosis and treatment of infectious syphilis in Canada: a cross-sectional study

ObjectivesSingle-visit testing and treatment for syphilis can reduce follow-up visits. The objectives of this study were to evaluate the performance and treatment outcomes of two dual syphilis/HIV point-of-care tests (POCTs). MethodsParticipants aged 16 years and older were offered concurrent syphilis/HIV POCTs with fingerstick blood sampling using two extremely rapid (<5 minutes) devices (MedMira Multiplo Rapid TP/HIV test and INSTI Multiplex HIV-1/HIV-2/Syphilis Antibody Test). Those with positive POCT results were offered same-day syphilis treatment and linkage to HIV care. Nurses performed testing at two emergency departments, a First Nations community, a correctional facility, and a sexually transmitted infection clinic. POCT results were compared with those of standard serological testing. Sensitivity and specificity were calculated. ResultsBetween August 2020 and February 2022, 1526 visits were completed. Both POCTs accurately identified participants with HIV (sensitivity, 100% [24 of 24]; 95% CI, 86.2–100%; specificity, 99.6% [1319 of 1324]; 95% CI, 99.1–99.8%), linking 24 HIV cases to care. Both tests were most sensitive with a rapid plasma reagin (RPR) of ≥1:8 dilutions (Multiplo: sensitivity, 98.3% [231 of 235]; 95% CI, 95.7–99.3%; specificity, 99.5% [871 of 875]; 95% CI, 98.8–99.8%; INSTI Multiplex: sensitivity, 97.9% [230 of 235]; 95% CI, 95.1–99.1%; specificity, 99.8% [873 of 875]; 95% CI, 99.2–99.9%) and least sensitive with non-reactive RPR (Multiplo: sensitivity, 54.1% [59 of 109]; 95% CI, 44.8–63.2%; specificity, 99.5% [871 of 875]; 95% CI, 98.8–99.8%; INSTI Multiplex: sensitivity, 28.4% [31 of 109]; 95% CI, 20.8–37.5%; specificity, 99.8% [873 of 875]; 95% CI, 99.2–99.9%). Eighty-five percent of participants with infectious syphilis were treated on the same day as the positive POCT result. DiscussionTwo extremely rapid (<5 minutes) dual syphilis/HIV POCTs showed excellent sensitivity and specificity for the diagnosis of active syphilis (RPR, ≥1:8 dilutions) and HIV and confirmed the ability to offer single-visit testing and treatment for syphilis and linkage to HIV care in diverse clinical settings.

A Pliocene Precipitation Isotope Proxy-Model Comparison Assessing the Hydrological Fingerprints of Sea Surface Temperature Gradients.

The Pliocene offers insights into future climate, with near-modern atmospheric pCO2 and global mean surface temperature estimated to be 3-4°C above pre-industrial. However, the hydrological response differs between future global warming and early Pliocene climate model simulations. This discrepancy results from the use of reduced meridional and zonal sea surface temperature (SST) gradients, based on foraminiferal Mg/Ca and Alkenone proxy evidence, to force the early Pliocene simulation. Subsequent, SST reconstructions based on the organic proxy TEX86, have found warmer temperatures in the warm pool, bringing the magnitude of the gradient reductions into dispute. We design an independent test of Pliocene SST scenarios and their hydrological cycle "fingerprints." We use an isotope-enabled General Circulation Model, iCAM5, to model the distribution of water isotopes in precipitation in response to four climatological SST and sea-ice fields representing modern, abrupt 4×CO2, late Pliocene and early Pliocene climates. We conduct a proxy-model comparison with all the available precipitation isotope proxy data, and we identify target regions that carry precipitation isotopic fingerprints of SST gradients as priorities for additional proxy reconstructions. We identify two regions with distinct precipitation isotope (D/H) fingerprints resulting from reduced SST gradients: the Maritime Continent (D-enriched due to reduced convective rainfall) and the Sahel (wetter, more deep convection, D-depleted). The proxy-model comparison using available plant wax reconstructions, mostly from Africa, is promising but inconclusive. Additional proxy reconstructions are needed in both target regions and in much of the world for significant tests of SST scenarios and dynamical linkages to the hydrological cycle.

Testing a social network approach to promote HIV self-testing and linkage to care among fishermen at Lake Victoria: study protocol for the Owete cluster randomized controlled trial

BackgroundNearly 50% of men living with HIV in many countries are unaware of their HIV status; men also have lower uptake of HIV treatment and pre-exposure prophylaxis (PrEP). In SSA, highly mobile men such as those working in fishing communities alongside Lake Victoria have low uptake of HIV testing and low rates of linkage to HIV treatment and PrEP, despite increasing availability of these services. HIV self-testing (HIVST) kits hold promise for overcoming barriers to HIV testing and linkage to services for HIV-positive and HIV-negative men. We describe here a protocol for an HIV status-neutral, social network-based approach to promote HIV testing, linkage to care and prevention, and better health outcomes, including adherence, in fishermen around Lake Victoria.MethodsUtilizing beach management unit (BMU) registries of fishermen operating in three Lake Victoria fishing communities in Siaya County, Kenya, we completed a census and social network mapping to identify close social networks of men. Network clusters identified by a socially-central lead (“promotor”) and selected to ensure maximal separation between treatment and control will be randomized. Promotors in both arms will receive basic HIV training; intervention promotors are further trained in HIVST to distribute kits to their cluster, while control promotors will distribute to their cluster vouchers for free HIVST at nearby clinics. We will test whether these promoters can enhance linkage to ART and PrEP after self-testing, thereby addressing a key limitation of HIVST. We will also measure 6- and 12-month viral load in those living with HIV and PrEP adherence among those without HIV via urine tenofovir levels as objective markers of adherence.DiscussionThis study has the potential to improve HIV health and promote HIV prevention among a hard to reach, at-risk, and highly mobile population of men in Western Kenya—a critical population in Kenya’s HIV prevention and treatment program. Further, if successful, this innovative social networks-based model could be scaled at the regional level to address HIV prevention and care among similarly at-risk populations of men in eastern Africa and inland fisheries settings across the continent.Trial registrationSelf-Test Strategies and Linkage Incentives to Improve ART and PrEP Uptake in Men, registered on February 26, 2021, registration #NCT04772469.

A Path Towards Green Revolution: How do Environmental Technologies, Political Risk, and Environmental Taxes Influence Green Energy Consumption?

Enhancing green energy consumption is the most important strategy to achieve environmental goals and control global temperature rise. Unquestionably, political intuitions make decisions for developing environmental technologies and imposing environmental taxes for phasing out fossil fuels and achieving energy transition. Therefore, this study explores the role of environmental technologies, political risk, and environmental taxes in green energy consumption considering the potential impacts of population density and economic growth in G7 countries. Second-generation tests are applied for analyzing the long-run equilibrium connection and stationarity features. Finally, the CuP-FM and CuP-BC estimators are applied for assessing long-run linkage and Dumitrescu-Hurlin causal test is applied to reveal causal flow among variables. The estimates uncovered that enhancing environmental technologies and environmental taxes upsurges the consumption of green energy. Reducing political risk in G7 countries also boosts green energy consumption. Economic growth is evidenced to stimulate the consumption of green energy, while population density limits the consumption of green energy. Moreover, environmental technologies and political risk Granger cause green energy utilization, while a feedback relationship exists between environmental taxes and green energy usage. Based on the results, this study suggests that G7 countries should allocate more funds to accelerate innovation in environmental technologies and, at the same time, reduce the political risk to boost green energy consumption.

Do leaf nitrogen resorption dynamics align with the slow‐fast continuum? A test at the intraspecific level

Abstract The links between internal nitrogen recycling through the process of resorption from senescing leaves, whole‐plant resource‐use strategies and performance remain elusive. Indeed, tests of such potential linkages are hampered by the classical evaluation of plant nitrogen resorption efficiency (REN) based on ‘snapshots’ of leaf nitrogen concentration from adult and senescent leaves. We significantly increased the resolution for measuring leaf nitrogen resorption by non‐destructively tracking time courses of nitrogen concentration in leaves of 137 natural Arabidopsis thaliana genotypes native to a wide range of climates across Europe, grown in a greenhouse. In addition to the classical measurement of resorption efficiency, we computed the relative maximum resorption rate of nitrogen (RRN), that is, the amount of nitrogen remobilized by a leaf per unit time and per unit nitrogen, together with slow–fast syndrome traits at the leaf and whole‐plant levels. Across genotypes, high rates and efficiencies of nitrogen resorption were associated with low specific leaf area and late flowering. The RRN showed significant heritability, genetic associations and was negatively correlated with the mean annual temperature of the native populations. By contrast, despite the evidence of a correlation with temperature, REN showed lower heritability and no evidence of genetic association, questioning the mechanisms of nitrogen resorption. Overall, our results suggest a much stronger adaptive role for leaf nitrogen resorption than previously uncovered. Read the free Plain Language Summary for this article on the Journal blog.

Distribution of weighted Lancaster’s statistic for combining independent or dependent P-values, with applications to human genetic studies

The meta-analysis of P-values is a widely used method in integrating information from multiple studies, and much research has focused on combining P-values. Among the established approaches, Fisher's test may be the most popular one. Many studies have been devoted to extending or modifying Fisher's statistic. For example, Lancaster’s variation of Fisher’s method may outperform the weighted Z-test and recently has drawn noteworthy attention. In this study, we first extend Lancaster's statistic by incorporating a weighting scheme. An approximation and an algorithm that are suitable for use under both independence and dependence assumptions are proposed for calculating the distribution of the weighted Lancaster statistic. The relationships between this method and existing ones are discussed. An application of the main results to a linkage test method in human gene mapping is then provided to show its use.

Hepatitis C Virus Infection in Eastern Libya: Efforts Needed to Improve HCV Testing and Linkage to Care in the Resource-Limited Setting.

Hepatitis C virus (HCV) is a significant public health problem, and the elimination of its infection by 2031 is a global goal. However, due to insufficient testing, lack of linkage to care (LTC) and treatment, Libya may be far from achieving this goal. This study aimed to explore HCV testing, the care and treatment of infected people, and to assess the burden of the infection among individuals who visited the main Medical Centre in Tobruk region, eastern Libya, for various medical and surgical conditions. A research team interviewed public health officials in Tobruk Medical Center, inspected available equipment, and obtained data available for people who were positive for antibodies to HCV (anti-HCV) as part of their routine pre-invasive procedures and pre-donation screening tests from January 2005 to April 2020. HCV antibody tests were positive for 612 cases out of 368,392 (0.17%). Of those who tested positive for anti-HCV antibodies, no one had followed up by RNA test for identifying individuals with chronic HCV infection, and there are no links to outpatient care and treatment. Our findings highlight the critical need for an up-to-date HCV diagnosis and linkage to care guidelines, which includes a follow-up RNA test for anti-HCV positive patients and early linkage to care for confirmed cases to accelerate the elimination of HCV infection from the community.

A micro hexapod robot for swarm applications assembled from a single FPC sheet

In recent years, micro robots have been actively studied for swarm applications. For example, micro hexapod robots have remarkable mobility on rough terrains. To apply micro hexapod robots in swarm explorations, the fabrication costs of the robots must be reduced. In this study, we propose a hexapod robot for swarm applications, assembled from a single flexible printed circuit (FPC) sheet. The necessary components for swarm applications (the body frame, legs, micro actuators, walking linkages, driving circuits, and microcontroller) are integrated into one FPC sheet. Our robot is assembled by folding one FPC sheet, and eliminating the need to handle and align multiple components during assembly. Thus, the robot can be fabricated cost effectively in short time. Moreover, we perform a driving test of the walking linkage and a walking test of the hexapod robot to demonstrate its effectiveness.

Closer to reality? The application of sequence analysis in crime linkage

PurposeTraditional crime linkage studies on serial sexual assaults have relied predominantly on a binary crime linkage approach that has yielded successful results in terms of linkage accuracy. Such an approach is a coarse reflection of reality by focussing mainly on the outcome of an offence, neglecting the forceful differences due to the intricate offender-victim interaction. Only few researchers have examined sexual assaults through the lens of a sequence analysis framework. This paper aims to present the first empirical test of offence sequence-based crime linkage, moving beyond exploratory analyses.Design/methodology/approachOffence accounts from 90 serial sexual assault and rape victims from the UK were analysed and sequentially coded. Sequence analysis allowed to compare all offences combinations regarding their underlying sequence of events. The resulting comparison was transformed and plotted in two-dimensional space by multidimensional scaling analysis for a visual inspection of linkage potential. The transformed proximities of all offences were used as predictors in a receiver operating characteristic analysis to actually test their discriminatory accuracy for crime linkage purpose.FindingsSequence analysis shows significant discriminatory accuracy for crime linkage purpose. However, the method does perform less well than previous binary crime linkage studies.Research limitations/implicationsSeveral limitations due to the nature of the data will be discussed.Practical implicationsThe practical limitations are as follows: the study is a potential practical value for crime analysts; it is a complimentary methodology for statistical crime linkage packages; it requires automated coding to be useful; and it is very dependent on crime recoding standards.Originality/valueThe exploratory part of this study has been published in a book chapter in 2015. However, to the best of the authors’ knowledge, the succinct test of crime linkage accuracy is the first of its kind.

An Axiom SNP genotyping array for Douglas-fir

BackgroundIn forest trees, genetic markers have been used to understand the genetic architecture of natural populations, identify quantitative trait loci, infer gene function, and enhance tree breeding. Recently, new, efficient technologies for genotyping thousands to millions of single nucleotide polymorphisms (SNPs) have finally made large-scale use of genetic markers widely available. These methods will be exceedingly valuable for improving tree breeding and understanding the ecological genetics of Douglas-fir, one of the most economically and ecologically important trees in the world.ResultsWe designed SNP assays for 55,766 potential SNPs that were discovered from previous transcriptome sequencing projects. We tested the array on ~ 2300 related and unrelated coastal Douglas-fir trees (Pseudotsuga menziesii var. menziesii) from Oregon and Washington, and 13 trees of interior Douglas-fir (P. menziesii var. glauca). As many as ~ 28 K SNPs were reliably genotyped and polymorphic, depending on the selected SNP call rate. To increase the number of SNPs and improve genome coverage, we developed protocols to ‘rescue’ SNPs that did not pass the default Affymetrix quality control criteria (e.g., 97% SNP call rate). Lowering the SNP call rate threshold from 97 to 60% increased the number of successful SNPs from 20,669 to 28,094. We used a subset of 395 unrelated trees to calculate SNP population genetic statistics for coastal Douglas-fir. Over a range of call rate thresholds (97 to 60%), the median call rate for SNPs in Hardy-Weinberg equilibrium ranged from 99.2 to 99.7%, and the median minor allele frequency ranged from 0.198 to 0.233. The successful SNPs also worked well on interior Douglas-fir.ConclusionsBased on the original transcriptome assemblies and comparisons to version 1.0 of the Douglas-fir reference genome, we conclude that these SNPs can be used to genotype about 10 K to 15 K loci. The Axiom genotyping array will serve as an excellent foundation for studying the population genomics of Douglas-fir and for implementing genomic selection. We are currently using the array to construct a linkage map and test genomic selection in a three-generation breeding program for coastal Douglas-fir.

Prolificacy genes in sheep: the French genetic programmes

It has been demonstrated that variations in litter size or ovulation rate in different breeds of sheep can be associated with the segregation of several major genes. This set of natural mutants constitutes a valuable resource to determine key points in the biochemical pathways controlling the development of ovarian follicles. The French genetic programmes were devised to identify two of these genes: the Booroola (FecB) and Lacaune genes. The FecB prolific mutation corresponds to a non-conservative mutation (Q249R) in the intracellular kinase-signalling domain of the bone morphogenetic protein receptor type IB (BMPR-IB) gene. The Lacaune gene is situated on ovine chromosome 11. Positional cloning is currently in progress to identify the relevant gene and mutation. A similar approach, limited to linkage testing of candidate genes, is proposed to classify the different prolificacy genes in sheep.

Linkage to care among adults being investigated for tuberculosis in South Africa: pilot study of a case manager intervention

ObjectivesWe piloted an intervention to determine if support from a case manager would assist adults being investigated for tuberculosis (TB) to link into TB and HIV care.DesignPilot interventional cohort study.Participants...

Test of Linkage between Governance Style and National Economic Indices

The relationship between the deliberate reinvention of the wheel, for macroeconomic indices such as interest rate, inflation, exchange rate, stock prices, index of industrial output within the electoral windows and the political parties’ (incumbent and opposition) ideology is the focus of this study. Monthly macroeconomic data for UK, USA, Japan, China, Hong Kong, Egypt, South Africa, Brazil, Nigeria, France and Germany from Morgan Stanley Capital International (MSCI) as well as World Bank for the period of 2000-2015 were used in the study. Employing majorly, the dynamic Genaralized Method of Moment (GMM) estimation technique, the study reveals that the coefficients of partisanship effects have the same negative signs and is significant for all the countries except Nigeria and Egypt. Also, the coefficients are similar in terms of size (US and China). Hence, the results show that party orientation does have significant impact on stock market returns of the selected countries with greater impact on Nigeria and Egypt. Strengthening the various regulatory agencies in charge of these macroeconomic policies is recommended to avoid this uncessary manoeuvring in governance. We are of the view that automation of capital markets activities will reduce the chances of manipulating capital market economic data.

Contribution of Inbred Singletons to Variance Component Estimation of Heritability and Linkage

Objectives: An interesting consequence of consanguinity is that the inbred singleton becomes informative for genetic variance. We determine the contribution of an inbred singleton to variance component analysis of heritability and linkage. Methods: Statistical theory for the power of variance component analysis of quantitative traits is used to determine the expected contribution of an inbred singleton to likelihood-ratio tests of heritability and linkage. Results: In variance component models, an inbred singleton contributes relatively little to a test of heritability but can contribute substantively to a test of linkage. For small-to-moderate quantitative trait locus (QTL) effects and a level of inbreeding comparable to matings between first cousins (the preferred form of union in many human populations), an inbred singleton can carry nearly 25% of the information of a non-inbred sib pair. In more highly inbred contexts available with experimental animal populations, nonhuman primate colonies, and some human subpopulations, the contribution of an inbred singleton relative to a sib pair can exceed 50%. Conclusions: Inbred individuals, even in isolation from other members of a sample, can contribute to variance component estimation and tests of heritability and linkage. Under certain conditions, the informativeness of the inbred singleton can approach that of a non-inbred sib pair.

Low‐δ18O Rhyolites From the Malani Igneous Suite: A Positive Test for South China and NW India Linkage in Rodinia

AbstractThe Malani igneous suite (MIS) in NW India represents one of the best preserved silicic large igneous provinces. Voluminous silicic lavas of the MIS erupted between ~780–750 Ma. Zircon grains from rhyolite and dacite lavas have oxygen isotopic compositions that include depleted (δ18O = 4.12 to −1.11‰) and enriched (δ18O = 8.23–5.12‰) signatures. The low‐δ18O zircon grains have highly radiogenic Hf isotopic compositions (ƐHf(t) = +13.0 to +3.6), suggesting high‐temperature bulk cannibalization of upper level juvenile mafic crust as an essential mechanism to produce the low‐δ18O felsic magma. Xenocrystic zircon grains in dacites have high δ18O and low ƐHf(t) values for magmas older than 800 Ma, reflecting a dramatic transition in tectono‐thermal regime in NW India during 800–780 Ma. A synchronous transition also occurred in south China and Madagascar, suggesting a spatially linked geodynamic system. NW India and south China together with Madagascar and the Seychelles lay either along the periphery of Rodinia or outboards of the supercontinent with the age of convergent plate margin magmatism coinciding with breakup of the supercontinent.

Identifying novel fruit-related genes in Arabidopsis thaliana based on the random walk with restart algorithm.

Fruit is essential for plant reproduction and is responsible for protection and dispersal of seeds. The development and maturation of fruit is tightly regulated by numerous genetic factors that respond to environmental and internal stimulation. In this study, we attempted to identify novel fruit-related genes in a model organism, Arabidopsis thaliana, using a computational method. Based on validated fruit-related genes, the random walk with restart (RWR) algorithm was applied on a protein-protein interaction (PPI) network using these genes as seeds. The identified genes with high probabilities were filtered by the permutation test and linkage tests. In the permutation test, the genes that were selected due to the structure of the PPI network were discarded. In the linkage tests, the importance of each candidate gene was measured from two aspects: (1) its functional associations with validated genes and (2) its similarity with validated genes on gene ontology (GO) terms and KEGG pathways. Finally, 255 inferred genes were obtained, subsequent extensive analysis of important genes revealed that they mainly contribute to ubiquitination (UBQ9, UBQ8, UBQ11, UBQ10), serine hydroxymethyl transfer (SHM7, SHM5, SHM6) or glycol-metabolism (HXKL2_ARATH, CSY5, GAPCP1), suggesting essential roles during the development and maturation of fruit in Arabidopsis thaliana.

High quality linkage using Multibit Trees for privacy-preserving blocking

ABSTRACT&#x0D; ObjectivesAs privacy-preserving record linkage (PPRL) emerges as a method for linking sensitive data, efficient blocking techniques that help maintain high levels of linkage quality are required. This research looks at the use of a Q-gram Fingerprinting blocking technique, with Multibit Trees, and applies this method to real-world datasets.&#x0D; ApproachData comprised ten years of hospital and mortality records from several Australian states, totalling over 25 million records. Each record contained a linkage key, as defined by the jurisdiction, which was used to assess quality (i.e. used as a ‘gold standard’). Different parameter sets were defined for the linkage tests with a privacy-preserved file created for each parameter set. The files contained jurisdictional linkage key and a Cryptographic Long-term Key (the CLK is a Bloom filter comprising all fields in the parameter set).&#x0D; Each file was run through an implementation of the Q-gram Fingerprinting blocking algorithm as a deduplication technique, using different similarity thresholds. The quality metrics of precision, recall and f-measure were calculated.&#x0D; ResultsResultant quality varied for each parameter set. Adding suburb and postcode reduced the linkage quality. The best parameter set returned an F-measure of 0.951. In general, precision was high in all settings, but recall fell as more fields were added to the CLK. We will report details for all parameter settings and their corresponding results.&#x0D; ConclusionThe Q-gram Fingerprinting blocking technique shows promise for maintaining high quality linkage in reasonable time. Determining which fields to include in the CLK for the linkage of specific datasets is important to maximise linkage quality, as well as selecting optimal similarity thresholds. Developing new technology is important for progressing the implementation of PPRL in real-world settings.

Model-Free Linkage Analysis of a Binary Trait.

Genetic linkage analysis aims to detect chromosomal regions containing genetic variants that influence risk of specific inherited diseases. The presence of linkage is indicated when a disease or trait cosegregates through the families with genetic markers at a particular region of the genome. Two main types of genetic linkage analysis are in common use, namely model-based linkage analysis and model-free linkage analysis. In this chapter, we focus solely on the latter type and specifically on binary traits or phenotypes, such as the presence or absence of a specific disease. Model-free linkage analysis is based on allele-sharing, where patterns of genetic similarity among affected relatives are compared to chance expectations. Because the model-free methods do not require the specification of the inheritance parameters of a genetic model, they are preferred by many researchers at early stages in the study of a complex disease. We introduce the history of model-free linkage analysis in Subheading 1. Table 1 describes a standard model-free linkage analysis workflow. We describe three popular model-free linkage analysis methods, the nonparametric linkage (NPL) statistic, the affected sib-pair (ASP) likelihood ratio test, and a likelihood approach for pedigrees. The theory behind each linkage test is described in this section together with a simple example of the relevant calculations. Table 4 provides a summary of popular genetic analysis software packages that implement model-free linkage models. In Subheading 2, we work through the methods on a rich example providing sample software code and output. Subheading 3 contains notes with additional details on various topics that may need further consideration during analysis.