MOD Scores Research Articles

Good functional results with open reduction and internal fixation for locked posterior shoulder fracture-dislocation: a case series.

There is no standardized therapeutic strategy for locked posterior shoulder fracture-dislocation (PSFD), and no consensus exists on the analysis of preoperative factors. This retrospective study aimed to evaluate functional results and complications in a series of PSFD cases managed with open surgical treatment. Patients diagnosed with locked PSFD who underwent open surgical treatment with reduction and osteosynthesis between April 2016 and March 2020 were included. All participants were treated with open reduction and internal fixation. Functional assessment used the modified University of California, Los Angeles (UCLA) mod scale, American Shoulder and Elbow Surgeons (ASES) questionnaire, subjective shoulder value (SSV), and visual analog scale (VAS). Complications were evaluated clinically and radiologically by X-ray and computed tomography. Twelve shoulders were included (11 patients; mean age, 40.6 years; range, 19- 62 years). The mean follow-up duration was 23.3 months (range, 12-63 months). The UCLA mod, ASES, SSV, and VAS scores were 29.1±3.7, 81.6±13.5, 78±14.8, and 1.2±1.4 points, respectively. The overall complication rate was 16.6%, with one case of post-traumatic stiffness, 1 case of chronic pain, and no cases of avascular necrosis. Open surgical treatment of locked PSFD can achieve good functional results. A correct understanding of these injuries and good preoperative planning helped us to achieve a low rate of complications.

A54 DIETARY COMPONENTS ARE ASSOCIATED WITH FECAL CALPROTECTIN IN ULCERATIVE COLITIS

BackgroundUlcerative colitis (UC) is thought to arise from dysregulated immune responses due to intestinal dysbiosis and altered epithelial barrier function. Dietary components may affect the gut microbiome and contribute to either inflammation or its resolution. The relationship between diet and disease activity in UC warrants further investigation.AimsThis prospective cohort study explored the relationship between dietary components, and markers of disease activity: fecal calprotectin (FCP) and partial Mayo score (PMS) in patients with UC.Methods40 participants were recruited from University of Calgary IBD clinics. Study staff obtained two 24-hour diet recalls using the validated automated self administered (ASA)-24 and captured PMS at baseline (T1) and follow-up at week 12 (T2). FCP samples were collected at T1 and T2. Diet variables included adjusted macro/micronutrients (n=44), food groups (n=36) and the validated Canadian healthy eating index-2009 (CHEI) where higher scores reflect healthier intake. CHEI captures intake of dark green and orange foods (DGO) and moderation scoring (MOD) of saturated fats (SF), sodium and added sugars. Higher CHEI scores result from increased intake of DGO and lower intake of SF, sodium and added sugars (higher MOD score). Associations with outcome variables were examined at T1 and T2 individually and across both timepoints (BT). Mixed effect logistic regression models identified relationships between dietary variables, FCP and PMS. Models were adjusted for age, sex, BMI, medications, probiotics, and for repeated measures in both timepoint analyses.ResultsA positive association was identified between FCP as a continuous variable and SF (T1:Coef=0.22, p_adj=0.02) and a negative association identified between FCP with citrus/melon/berries (BT:Coef=-1.01, p_adj =0.04), total sugars (BT:Coef=-0.06, p_adj=0.025) and HEI (BT:Coef=-0.13, p_adj =0.06 and T1 coef=-0.18, p_adj =7.0 e-5). FCP increased as SF (-0.30,p_adj=0.01), DGO (-0.60, p_adj=0.02), and MOD (-0.21, p_adj=0.02) scores decreased. The presence of inflammation (as a binary variable, FCP >250) was negatively associated with higher fiber intake (BT: Odds Ratio (OR)= 0.016, CI(0.001,0.40) p_adj=0.08). For PMS as a continuous variable, HEI had a negative association with PMS (T2: -0.05, p_adj=0.06). With PMS as a discrete score (remission=PMS<2) there was no significant association with any diet components.ConclusionsThis study suggests that a healthier diet, both in overall pattern and specific dietary components, was associated with lower FCP and PMS. Our findings related to SF, citrus/melons/berries, and DGO parallel the IOIBD dietary guidelines. Future research should explore through controlled intervention studies whether modifying dietary patterns and components independently reduces disease activity. Funding AgenciesCrohn’s and Colitis Foundation

A Functional Variant of CXCL16 Is Associated With Predisposition to Sepsis and MODS in Trauma Patients: Genetic Association Studies.

PurposeCXC chemokines are mediators which mediate immune cells migration to sites of inflammation and injury. Chemokine C-X-C motif ligand 16 (CXCL16) plays an important role in the occurrence and development of sepsis through leukocyte chemotaxis, leukocyte adhesion and endotoxin clearance. In this study, we selected a set of tagging single nucleotide polymorphisms (tag SNPs) in the CXCL16 gene and investigated their clinical relevance to the development of sepsis and multiple organ dysfunction syndrome (MODS) in patients with major trauma in three independent Chinese Han populations.MethodsA total of 1,620 major trauma patients were enrolled in this study. Among these patients, 920 came from Chongqing in western China, 350 came from Zhejiang Province in eastern China, and 350 came from Guizhou Province in southwestern China. The improved multiplex ligation detection reaction (iMLDR) method was employed in the genotyping and genetic association analyses to determine the associations between CXCL16 haplotypes and sepsis morbidity rate and higher MOD scores in three cohorts.ResultsOnly CXCL16 T123V181 haplotype was associated with an increased risk for sepsis morbidity and higher MOD scores in the three cohorts (OR = 1.89, P = 0.001 for the Chongqing cohort; OR = 1.76, P = 0.004 for the Zhejiang cohort; OR = 1.55, P = 0.012 for the Guizhou cohort). The effect of T123V181 haplotype on the chemotaxis, migration and endotoxin clearance of immune cells were further observed. Protein modeling analysis showed that T123 and V181 might alter the structure of the CXCL16 active center. Thus it enhanced the chemotaxis and adhesion ability of immunocytes.ConclusionWe demonstrate the mechanism of CXCL16 T123V181 haplotype which regulates the sepsis morbidity rate and thus provide a new biomarker for early diagnosis of sepsis and MODS.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT01713205 (https://www.clinicaltrials.gov/ct2/results?cond=&term=+NCT01713205&cntry=&state=&city=&dist=).

Definition of fibromyalgia severity: findings from a cross-sectional survey of 2339 Italian patients.

To establish optimal cut-off values for the scores of the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromialgia Assessment Scale (FAS 2019mod), and the Polysymptomatic Distress Scale (PDS) in order to distinguish five levels of FM disease severity. Consecutive FM patients were evaluated with the three clinimetric indices, and each patient was required to answer the anchor question: 'In general, would you say your health is 1 = very good, 2 = good, 3 = fair, 4 = poor, or 5 = very poor?'-which represented the external criterion. Cut-off points were established through the interquartile reconciliation approach. The study sample consisted of 2181 women (93.2%) and 158 men (6.8%), with a mean age of 51.9 (11.5) years, and mean disease duration was 7.3 (6.9) years. The overall median FIQR, FAS 2019 mod and PDS scores (25th-75th percentiles) were respectively 61.16 (41.16-77.00), 27.00 (19.00-32.00) and 19.0 (13.00-24.00). Reconciliation of the mean 75th and 25th percentiles of adjacent categories defined the severity states for FIQR: 0-23 for remission, 24-40 for mild disease, 41-63 for moderate disease, 64-82 for severe disease and >83 for very severe disease; FAS 2019 mod: 0-12 for remission, 13-20 for mild disease, 21-28 for moderate disease, 29-33 for severe disease and >33 for very severe disease; PDS: 0-5 for remission, 6-15 for mild disease, 16-20 for moderate disease, 21-25 for severe disease and >25 for very severe disease. Disease severity cut-offs can represent an important improvement in interpreting FM.

Rs1982809 is a functional biomarker for the prognosis of severe post-traumatic sepsis and MODs.

BTLA is a useful biomarker to characterize the immune states of sepsis patients. We investigated the association between genetic variations of BTLA and morbidity of sepsis and MODS in severe traumatic patient. Three tag single nucleotide polymorphisms of BTLA were genotyped in 562 severe trauma patients. To further elucidate the mechanism, mRNA stability, BTLA 3ʹ-UTR activity, and its expression on T lymphocytes were measured. Only rs1982809 which located in 3ʹ-UTR of BTLA showed a significant clinical relevance with the incidence rate of sepsis and MOD scores. The sepsis incidence and MOD score of rs1982809 CC genotype carriers were higher than TT carriers. The percentage of circulating BTLA + CD4 + CD3 + T lymphocytes was markedly lower in CC genotype carriers. Luciferase activity in plasmids containing C allele was lower than that of T allele. Thus, the differential expression of BTLA on T lymphocytes might be caused by the different 3ʹ-UTR activity induced by rs1982809 T/C. Therefore, rs1982809 is a useful clinical biomarker in the prognosis evaluating of sepsis and subsequent MODS. Moreover, it is also a functional single nucleotide polymorphism affecting the activity of BTLA 3ʹ-UTR and the expression of BTLA in peripheral blood T lymphocytes. Impact statement This work is useful in the field of genetic mechanism of severe post-traumatic complications, as it provides important evidence for the influence of BTLA gene polymorphism on sepsis and MODS susceptibility. The results are useful and of importance because rs1982809 is a useful clinical biomarker in the prognosis evaluating of sepsis and subsequent MODS. It is also a functional single nucleotide polymorphism affecting the activity of BTLA 3ʹ-UTR and the expression of BTLA in peripheral blood T lymphocytes.

Predicting the Destiny after Severe Traumatic Brain Injury; Multi Organ Dysfunction Syndrome (MODS) or Sequential Organ Failure Assessment (SOFA)?

Purpose: To compare the outcome prediction ability of SOFA and MOD scoring systems, in the subset of ICU patients with severe traumatic brain injury. Materials and Methods: We performed a descriptive analytic study at Poursina hospital, a tertiary care trauma center. A number of 83 patients with severe traumatic brain injury who admitted to ICU between November 2012 and December 2013 were included. SOFA and MOD scores were calculated for each patient on a daily basis and areas under receiver operating characteristic curves were used to compare the discriminative ability of two scoring systems. Results: Out of 83 patients, 23 died (27.71%). AUROC curve for SOFA and MOD score were 0.514 and 0.510 respectively on admission, 0.587 and 0.512 on the second day of admission, 0.779 and 0.749 on the fourth day of admission and 0.978 and 0.824 after two weeks. Both systems were unreliable predictors of death for first 48 hours of admission. After 96 hours of admission, both systems represented an acceptable prediction ability, with no statistically significant difference between two tools (P value=0.850). In terms of outcome prediction, MOD scoring system performed good on fourteenth day with a significant difference when compared to excellent discriminant function of SOFA (P value=0.027). Conclusions: During the 48 hours of admission, none of scoring tools showed a reliable function of predicting the ICU mortality. They represented an acceptable discriminative ability after the fourth day of admission and better predictive ability after the fourteenth day of admission. After two weeks of admission, SOFA is superior to MODS in outcome prediction.

Early detection of nonneurologic organ failure in patients with severe traumatic brain injury: Multiple organ dysfunction score or sequential organ failure assessment?

Objective:The aim of this study is to compare the discriminant function of multiple organ dysfunction score (MODS) and sequential organ failure assessment (SOFA) components in predicting the Intensive Care Unit (ICU) mortality and neurologic outcome.Materials and Methods:A descriptive–analytic study was conducted at a level I trauma center. Data were collected from patients with severe traumatic brain injury admitted to the neurosurgical ICU. Basic demographic data, SOFA and MOD scores were recorded daily for all patients. Odd's ratios (ORs) were calculated to determine the relationship of each component score to mortality, and area under receiver operating characteristic (AUROC) curve was used to compare the discriminative ability of two tools with respect to ICU mortality.Results:The most common organ failure observed was respiratory detected by SOFA of 26% and MODS of 13%, and the second common was cardiovascular detected by SOFA of 18% and MODS of 13%. No hepatic or renal failure occurred, and coagulation failure reported as 2.5% by SOFA and MODS. Cardiovascular failure defined by both tools had a correlation to ICU mortality and it was more significant for SOFA (OR = 6.9, CI = 3.6–13.3, P < 0.05 for SOFA; OR = 5, CI = 3–8.3, P < 0.05 for MODS; AUROC = 0.82 for SOFA; AUROC = 0.73 for MODS). The relationship of cardiovascular failure to dichotomized neurologic outcome was not significant statistically. ICU mortality was not associated with respiratory or coagulation failure.Conclusion:Cardiovascular failure defined by either tool significantly related to ICU mortality. Compared to MODS, SOFA-defined cardiovascular failure was a stronger predictor of death. ICU mortality was not affected by respiratory or coagulation failures.

Fast Linkage Analysis with MOD Scores Using Algebraic Calculation

Objective: As the mode of inheritance is often unknown for complex diseases, a MOD-score analysis, in which the parametric LOD score is maximized with respect to the trait-model parameters, can be a powerful approach in genetic linkage analysis. Because the calculation of the disease-locus likelihood is the most time-consuming step in a MOD-score analysis, we aimed to optimize this part of the calculation to speed up linkage analysis using the GENEHUNTER-MODSCORE software package. Methods: Our new algorithm is based on minimizing the effective number of inheritance vectors by collapsing them into classes. To this end, the disease-locus-likelihood contribution of each inheritance vector is represented and stored in its algebraic form as a symbolic sum of products of penetrances and disease-allele frequencies. Simulations were used to assess the speedup of our new algorithm. Results: We were able to achieve speedups ranging from 1.94 to 11.52 compared to the original GENEHUNTER-MODSCORE version, with higher speedups for larger pedigrees. When calculating p values, the speedup ranged from 1.69 to 10.36. Conclusion: Computation times for MOD-score analysis, involving the evaluation of many tested sets of trait-model parameters and p value calculation, have been prohibitively high so far. With our new algebraic algorithm, such an analysis is now feasible within a reasonable amount of time.

A comparison of different linkage statistics in small to moderate sized pedigrees with complex diseases

BackgroundIn the last years GWA studies have successfully identified common SNPs associated with complex diseases. However, most of the variants found this way account for only a small portion of the trait variance. This fact leads researchers to focus on rare-variant mapping with large scale sequencing, which can be facilitated by using linkage information. The question arises why linkage analysis often fails to identify genes when analyzing complex diseases. Using simulations we have investigated the power of parametric and nonparametric linkage statistics (KC-LOD, NPL, LOD and MOD scores), to detect the effect of genes responsible for complex diseases using different pedigree structures.ResultsAs expected, a small number of pedigrees with less than three affected individuals has low power to map disease genes with modest effect. Interestingly, the power decreases when unaffected individuals are included in the analysis, irrespective of the true mode of inheritance. Furthermore, we found that the best performing statistic depends not only on the type of pedigrees but also on the true mode of inheritance.ConclusionsWhen applied in a sensible way linkage is an appropriate and robust technique to map genes for complex disease. Unlike association analysis, linkage analysis is not hampered by allelic heterogeneity. So, why does linkage analysis often fail with complex diseases? Evidently, when using an insufficient number of small pedigrees, one might miss a true genetic linkage when actually a real effect exists. Furthermore, we show that the test statistic has an important effect on the power to detect linkage as well. Therefore, a linkage analysis might fail if an inadequate test statistic is employed. We provide recommendations regarding the most favorable test statistics, in terms of power, for a given mode of inheritance and type of pedigrees under study, in order to reduce the probability to miss a true linkage.

Clinical relevance of single nucleotide polymorphisms of the high mobility group box 1 protein gene in patients with major trauma in Southwest China

High-mobility group box protein 1 (HMGB1) is a pivotal late mediator involved in the development of sepsis and multiple organ dysfunction syndrome (MODS) in critically ill patients. While several single nucleotide polymorphisms (SNPs) have been demonstrated to be critical determinants for outcome of critically ill patients, little is known about the clinical relevance of SNPs of the HMGB1 gene up to date. A total of 3 tag SNPs of the HMGB1 gene were selected using HapMap database and linkage disequilibrium analysis. The tag SNPs were genotyped using a pyrosequencing methodology in 556 unrelated patients with major trauma. Peripheral whole blood samples obtained immediately after admission were determined for HMGB1 production in response to exvivo lipopolysaccharide (LPS) stimulation. The rs2249825 SNP and the haplotype TCG were significantly associated with LPS-induced HMGB1 production by peripheral blood leukocytes. There were also significant differences in sepsis morbidity rate and MOD scores among patients with different genotypes of the rs2249825. In addition, the patients with the wild-type haplotype TCG had a lesser sepsis morbidity rate and MOD scores than those without the TCG haplotype. A total of 3 SNPs might act as tag SNPs for the entire HMGB1 gene. The rs2249825 and the haplotype TCG might be used as relevant risk estimate for the development of sepsis and MODS in patients with major trauma.

Development and use of a floristic quality index for coastal Louisiana marshes

The Floristic Quality Index (FQI) has been used as a tool for assessing the integrity of plant communities and for assessing restoration projects in many regions of the USA. Here, we develop a modified FQI (FQI(mod)) for coastal Louisiana wetlands and verify it using 12years of monitoring data from a coastal restoration project. Plant species that occur in coastal Louisiana were assigned a coefficient of conservatism (CC) score by a local group with expertise in Louisiana coastal vegetation. Species percent cover and both native and non-native species were included in the FQI(mod) which was scaled from 0-100. The FQI(mod) scores from the long-term monitoring project demonstrated the utility of this index for assessing wetland condition over time, including its sensitivity to a hurricane. Ultimately, the FQI developed for coastal Louisiana will be used in conjunction with other wetland indices (e.g., hydrology and soils) to assess wetland condition coastwide and these indices will aid managers in coastal restoration and management decisions.

Using Parametric Multipoint Lods and Mods for Linkage Analysis Requires a Shift in Statistical Thinking

Multipoint (MP) linkage analysis represents a valuable tool for whole-genome studies but suffers from the disadvantage that its probability distribution is unknown and varies as a function of marker information and density, genetic model, number and structure of pedigrees, and the affection status distribution [Xing and Elston: Genet Epidemiol 2006;30:447–458; Hodge et al.: Genet Epidemiol 2008;32:800–815]. This implies that the MP significance criterion can differ for each marker and each dataset, and this fact makes planning and evaluation of MP linkage studies difficult. One way to circumvent this difficulty is to use simulations or permutation testing. Another approach is to use an alternative statistical paradigm to assess the statistical evidence for linkage, one that does not require computation of a p value. Here we show how to use the evidential statistical paradigm for planning, conducting, and interpreting MP linkage studies when the disease model is known (lod analysis) or unknown (mod analysis). As a key feature, the evidential paradigm decouples uncertainty (i.e. error probabilities) from statistical evidence. In the planning stage, the user calculates error probabilities, as functions of one’s design choices (sample size, choice of alternative hypothesis, choice of likelihood ratio (LR) criterion k) in order to ensure a reliable study design. In the data analysis stage one no longer pays attention to those error probabilities. In this stage, one calculates the LR for two simple hypotheses (i.e. trait locus is unlinked vs. trait locus is located at a particular position) as a function of the parameter of interest (position). The LR directly measures the strength of evidence for linkage in a given data set and remains completely divorced from the error probabilities calculated in the planning stage. An important consequence of this procedure is that one can use the same criterion k for all analyses. This contrasts with the situation described above, in which the value one uses to conclude significance may differ for each marker and each dataset in order to accommodate a fixed test size, α. In this study we accomplish two goals that lead to a general algorithm for conducting evidential MP linkage studies. (1) We provide two theoretical results that translate into guidelines for investigators conducting evidential MP linkage: (a) Comparing mods to lods, error rates (including probabilities of weak evidence) are generally higher for mods when the null hypothesis is true, but lower for mods in the presence of true linkage. Royall [J Am Stat Assoc 2000;95:760–780] has shown that errors based on lods are bounded and generally small. Therefore when the true disease model is unknown and one chooses to use mods, one needs to control misleading evidence rates only under the null hypothesis; (b) for any given pair of contiguous marker loci, error rates under the null are greatest at the midpoint between the markers spaced furthest apart, which provides an obvious simple alternative hypothesis to specify for planning MP linkage studies. (2) We demonstrate through extensive simulation that this evidential approach can yield low error rates under the null and alternative hypotheses for both lods and mods, despite the fact that mod scores are not true LRs. Using these results we provide a coherent approach to implement a MP linkage study using the evidential paradigm.

Risk Factors for Organ Dysfunction and Failure in Patients with Acute Traumatic Cervical Spinal Cord Injury

Traumatic injuries to the cervical spine cause significant disability. Much of the morbidity and mortality that occurs in patients afflicted with cervical spinal cord injury (SCI) occurs early after injury due to primary neurologic dysfunction, systemic inflammation, concomitant injuries, treatments to prevent and ameliorate secondary insults, and prolonged immobilization. This study was undertaken to determine the incidence of organ dysfunction and failure using validated measures: the Multiple Organ Dysfunction Score (MODS) and the Sequential Organ Failure Assessment (SOFA). We also sought to determine if certain patient or injury characteristics were associated with the development of organ dysfunction and failure. All patients who sustained isolated blunt cervical SCIs admitted to the R Adams Cowley Shock Trauma Center over a 15-month period were identified. American Spinal Injury Association (ASIA) motor scores, ASIA impairment scale (AIS) scores, and level of injury were recorded. Admission, first daily, worst daily, and aggregate MOD and SOFA scores were assigned for each of six organ systems. A P < 0.05 was considered significant for all statistical tests. Of 1,028 patients admitted with blunt spine injuries between January, 2007 and March, 2008, 40 patients were identified with an isolated cervical SCI that required an ICU length of stay (LOS) >24 h. Organ failure of at least one organ system occurred in 75% of patients as calculated by MOD score and 85% of patients calculated using SOFA criteria. Multiple organ failure was found in 55% by MOD and 62.5% by SOFA scores. The most frequent system to fail was the cardiovascular system by aggregate MODS (84%), while the respiratory system was the most frequently failed system by aggregate SOFA criteria (70%). There was a strong inverse correlation between ASIA motor score and aggregate MODS and SOFA scores (r = -0.56, P = 0.0002 and r = -0.51, P = 0.0009). AIS was also found to be inversely correlated with the development of organ failure (r = -0.47, P = 0.002 and r = -0.45, P = 0.004) while anatomic level of injury was found to correlate poorly with the incidence of organ failure (r = -0.11, P = 0.5 and r = -0.10, P = 0.5). Only ASIA motor score was significantly associated with sum aggregate organ dysfunction scores when controlling for age and injury severity score (parameter estimate = -0.082, P = 0.0005 for MODS and parameter estimate = -0.057, P = 0.006 for SOFA). This study is the first to describe the incidence of organ dysfunction and failure in patients with isolated acute traumatic cervical SCI using validated organ system dysfunction scores. Respiratory, cardiovascular, neurologic, renal, hepatic, and hematologic dysfunction occurred commonly both on admission and over the ICU stay. Respiratory, cardiovascular, and neurologic failure were frequently found, while renal, hepatic, and hematologic failures were uncommon. Multiple organ failure occurred in the majority of patients. ASIA motor score and AIS were found to strongly correlate with the development of organ dysfunction and failure. Level of injury should be used with caution when describing the risk of complications and the need for medical interventions.

Clinical relevance of the interleukin 10 promoter polymorphisms in Chinese Han patients with major trauma: genetic association studies.

IntroductionAn excessive inflammatory response is thought to account for the pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS) after severe trauma. The interleukin-10 (IL-10) is a potent anti-inflammatory cytokine. The objectives of this prospective study were to investigate the distribution of IL-10 promoter polymorphisms in a cohort of 308 Chinese Han patients with major trauma, and to identify associations of IL-10 promoter polymorphisms with IL-10 production and incidence of sepsis and MODS.MethodsA total of 308 patients with major trauma were included in this study. The genotypes of polymorphisms -1082, -819 and -592 were determined by polymerase chain reaction-restriction fragment length polymorphism. The IL-10 levels in the supernatants were determined with enzyme-linked immunoabsorbent assay.ResultsThe -1082A and -592A alleles were significantly associated with lower lipopolysaccharide-induced IL-10 production in an allele-dose dependent fashion. There was no significant difference for the -819 polymorphism. Except for the -1082 polymorphism, the -819 and -592 polymorphisms were not significantly associated with sepsis morbidity rate and MOD scores.ConclusionsOur results further confirm the functionality of the IL-10 promoter single nucleotide polymorphisms in relation to IL-10 production. They also suggest that individual difference in IL-10 production in trauma patients might be at least in part related to genetic variations in the IL-10 promoter region.

Multipoint lods provide reliable linkage evidence despite unknown limiting distribution: type I error probabilities decrease with sample size for multipoint lods and mods

We investigate the behavior of type I error rates in model-based multipoint (MP) linkage analysis, as a function of sample size (N). We consider both MP lods (i.e., MP linkage analysis that uses the correct genetic model) and MP mods (maximizing MP lods over 18 dominant and recessive models). Following Xing and Elston (2006 Genet. Epidemiol, 30: 447-458), we first consider MP linkage analysis limited to a single position; then we enlarge the scope and maximize the lods and mods over a span of positions. In all situations we examined, type I error rates decrease with increasing sample size, apparently approaching zero. We show: (a) For MP lods analyzed only at a single position, well-known statistical theory predicts that type I error rates approach zero. (b) For MP lods and mods maximized over position, this result has a different explanation, related to the fact that one maximizes the scores over only a finite portion of the parameter range. The implications of these findings may be far-reaching: Although it is widely accepted that fixed nominal critical values for MP lods and mods are not known, this study shows that whatever the nominal error rates are, the actual error rates appear to decrease with increasing sample size. Moreover, the actual (observed) type I error rate may be quite small for any given study. We conclude that MP lod and mod scores provide reliable linkage evidence for complex diseases, despite the unknown limiting distributions of these MP scores.

Comparison of genome-wide single-nucleotide polymorphism linkage analyses in Caucasian and Hispanic NARAC families

We performed linkage analysis on families with rheumatoid arthritis, stratifying by ethnic origin. We compared results using either Kong and Cox nonparametric LOD scores or MOD score analysis using the software GeneHunter MODSCORE. We first applied SNPLINK to remove markers showing excess linkage disequilibrium from the SNPs in the Illumina IV SNP Linkage panel. In this analysis there were 659 self-reported Caucasian families and 29 self-reported Hispanic families in the NARAC collection. Chromosome 19 yielded MOD scores > 3.00 in the Hispanic group, while chromosomes 2, 6, 7, 11, and XY had MOD scores > 3.00 in the Caucasian group. We performed simulation studies to evaluate the empirical distribution of the MOD score for autosomal loci separately in Hispanics and Caucasians. Results showed genome-wide significant evidence for linkage in Caucasians for chromosomes 2q and 6p, but no significant evidence for any linkages in the Hispanics, including little evidence for linkage to chromosome 6p in this group. An examination of the difference of phenotypes in two ethnic groups suggested significantly earlier mean age of onset, higher percentage of anti-cyclic citrullinated peptide positive people, and lower percentage of affected people carrying shared epitopes in Hispanics than those in Caucasians. A larger sample size of the Hispanic group is needed to identify linkage regions.

Inferential testing for linkage with GENEHUNTER‐MODSCORE: The impact of the pedigree structure on the null distribution of multipoint MOD scores

The asymptotic distribution of [MOD] scores under the null hypothesis of no linkage is only known for affected sib pairs and other types of affected relative pairs. We have extended the GENEHUNTER-MODSCORE program to allow for simulations under the null hypothesis of no linkage to determine the empirical significance of MOD-score results in general situations. We performed simulations with families of different size (one million replicates of 500 families per simulation setting) to thoroughly investigate the impact of the pedigree size on the null distribution of multipoint MOD scores. It is shown that the distribution is dependent on the size and structure of the pedigrees under study. By performing simulations in the context of MOD-score analysis, our new tool efficiently explores the linkage data in a comprehensive way and also provides a valid method to inferentially test for linkage.

MOD-Score Analysis with Simple Pedigrees: An Overview of Likelihood-Based Linkage Methods

A MOD-score analysis, in which the parametric LOD score is maximized with respect to the trait-model parameters, can be a powerful method for the mapping of complex traits. With affected sib pairs, it has been shown before that MOD scores asymptotically follow a mixture of χ² distributions with 2, 1 and 0 degrees of freedom under the null hypothesis of no linkage. In that context, a MOD-score analysis yields some (albeit limited) information regarding the trait-model parameters, and there is a chance for an increased power compared to a simple LOD-score analysis. Here, it is shown that with unilineal affected relative pairs, MOD scores asymptotically follow a mixture of χ² distributions with 1 and 0 degrees of freedom under the null hypothesis, that is, the same distribution as followed by simple LOD scores. No information regarding the trait model can be obtained in this setting, and no power is gained when compared to a LOD-score analysis. An outlook to larger pedigrees is given. The number of degrees of freedom underlying the null distribution of MOD scores, that depends on the type of pedigrees studied, corresponds to the number of explored dimensions related to power and to the number of parameters that can jointly be estimated.

Distribution and magnitude of type I error of model‐based multipoint lod scores: implications for multipoint mod scores

The multipoint lod score and mod score methods have been advocated for their superior power in detecting linkage. However, little has been done to determine the distribution of multipoint lod scores or to examine the properties of mod scores. In this paper we study the distribution of multipoint lod scores both analytically and by simulation. We also study by simulation the distribution of maximum multipoint lod scores when maximized over different penetrance models. The multipoint lod score is approximately normally distributed with mean and variance that depend on marker informativity, marker density, specified genetic model, number of pedigrees, pedigree structure, and pattern of affection status. When the multipoint lod scores are maximized over a set of assumed penetrances models, an excess of false positive indications of linkage appear under dominant analysis models with low penetrances and under recessive analysis models with high penetrances. Therefore, caution should be taken in interpreting results when employing multipoint lod score and mod score approaches, in particular when inferring the level of linkage significance and the mode of inheritance of a trait.

Linkage analysis of alcohol dependence using MOD scores

Alcohol dependence is a typical example of a complex trait that is governed by several genes and for which the mode of inheritance is unknown. We analyzed the microsatellite markers and the Affymetrix single-nucleotide polymorphisms (SNPs) for a subset of the Collaborative Study on the Genetics of Alcoholism family sample, 93 pedigrees of Caucasian ancestry comprising 919 persons, 390 of whom are affected according to DSM III-R and Feighner criteria. In particular, we performed parametric single-marker linkage analysis using MLINK of the LINKAGE package (for the microsatellite data), as well as multipoint MOD-score analysis with GENEHUNTER-MODSCORE (for the microsatellite and SNP data). By use of two liability classes, different penetrances were assigned to males and females. In order to investigate parent-of-origin effects, we calculated MOD scores under trait models with and without imprinting. In addition, for the microsatellite data, the MOD-score analysis was performed with sex-averaged as well as sex-specific maps. The highest linkage peaks were obtained on chromosomes 1, 2, 7, 10, 12, 13, 15, and 21. There was evidence for paternal imprinting at the loci on chromosomes 2, 10, 12, 13, 15, and 21. A tendency to maternal imprinting was observed at two loci on chromosome 7. Our findings underscore the fact that an adequate modeling of the genotype-phenotype relation is crucial for the genetic mapping of a complex trait.