Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis

Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Fenger, Mogens [verfasserIn] Linneberg, Allan Werge, Thomas Jørgensen, Torben

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2008

Schlagwörter:	Insulin Resistance Metabolic Syndrome Structural Equation Modelling Oral Glucose Tolerance Test Physiological Variable

Anmerkung:	© Fenger et al; licensee BioMed Central Ltd. 2008

Übergeordnetes Werk:	Enthalten in: BMC genetics - London : BioMed Central, 2000, 9(2008), 1 vom: 08. Juli
Übergeordnetes Werk:	volume:9 ; year:2008 ; number:1 ; day:08 ; month:07

Links:	Volltext

DOI / URN:	10.1186/1471-2156-9-43

Katalog-ID:	SPR027004163

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245	1	0	\|a Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis
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520			\|a Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process.
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allfields	10.1186/1471-2156-9-43 doi (DE-627)SPR027004163 (SPR)1471-2156-9-43-e DE-627 ger DE-627 rakwb eng Fenger, Mogens verfasserin aut Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Fenger et al; licensee BioMed Central Ltd. 2008 Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. Insulin Resistance (dpeaa)DE-He213 Metabolic Syndrome (dpeaa)DE-He213 Structural Equation Modelling (dpeaa)DE-He213 Oral Glucose Tolerance Test (dpeaa)DE-He213 Physiological Variable (dpeaa)DE-He213 Linneberg, Allan aut Werge, Thomas aut Jørgensen, Torben aut Enthalten in BMC genetics London : BioMed Central, 2000 9(2008), 1 vom: 08. Juli (DE-627)326644938 (DE-600)2041497-3 1471-2156 nnns volume:9 year:2008 number:1 day:08 month:07 https://dx.doi.org/10.1186/1471-2156-9-43 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2008 1 08 07
spelling	10.1186/1471-2156-9-43 doi (DE-627)SPR027004163 (SPR)1471-2156-9-43-e DE-627 ger DE-627 rakwb eng Fenger, Mogens verfasserin aut Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Fenger et al; licensee BioMed Central Ltd. 2008 Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. Insulin Resistance (dpeaa)DE-He213 Metabolic Syndrome (dpeaa)DE-He213 Structural Equation Modelling (dpeaa)DE-He213 Oral Glucose Tolerance Test (dpeaa)DE-He213 Physiological Variable (dpeaa)DE-He213 Linneberg, Allan aut Werge, Thomas aut Jørgensen, Torben aut Enthalten in BMC genetics London : BioMed Central, 2000 9(2008), 1 vom: 08. Juli (DE-627)326644938 (DE-600)2041497-3 1471-2156 nnns volume:9 year:2008 number:1 day:08 month:07 https://dx.doi.org/10.1186/1471-2156-9-43 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2008 1 08 07
allfields_unstemmed	10.1186/1471-2156-9-43 doi (DE-627)SPR027004163 (SPR)1471-2156-9-43-e DE-627 ger DE-627 rakwb eng Fenger, Mogens verfasserin aut Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Fenger et al; licensee BioMed Central Ltd. 2008 Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. Insulin Resistance (dpeaa)DE-He213 Metabolic Syndrome (dpeaa)DE-He213 Structural Equation Modelling (dpeaa)DE-He213 Oral Glucose Tolerance Test (dpeaa)DE-He213 Physiological Variable (dpeaa)DE-He213 Linneberg, Allan aut Werge, Thomas aut Jørgensen, Torben aut Enthalten in BMC genetics London : BioMed Central, 2000 9(2008), 1 vom: 08. Juli (DE-627)326644938 (DE-600)2041497-3 1471-2156 nnns volume:9 year:2008 number:1 day:08 month:07 https://dx.doi.org/10.1186/1471-2156-9-43 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2008 1 08 07
allfieldsGer	10.1186/1471-2156-9-43 doi (DE-627)SPR027004163 (SPR)1471-2156-9-43-e DE-627 ger DE-627 rakwb eng Fenger, Mogens verfasserin aut Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Fenger et al; licensee BioMed Central Ltd. 2008 Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. Insulin Resistance (dpeaa)DE-He213 Metabolic Syndrome (dpeaa)DE-He213 Structural Equation Modelling (dpeaa)DE-He213 Oral Glucose Tolerance Test (dpeaa)DE-He213 Physiological Variable (dpeaa)DE-He213 Linneberg, Allan aut Werge, Thomas aut Jørgensen, Torben aut Enthalten in BMC genetics London : BioMed Central, 2000 9(2008), 1 vom: 08. Juli (DE-627)326644938 (DE-600)2041497-3 1471-2156 nnns volume:9 year:2008 number:1 day:08 month:07 https://dx.doi.org/10.1186/1471-2156-9-43 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2008 1 08 07
allfieldsSound	10.1186/1471-2156-9-43 doi (DE-627)SPR027004163 (SPR)1471-2156-9-43-e DE-627 ger DE-627 rakwb eng Fenger, Mogens verfasserin aut Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Fenger et al; licensee BioMed Central Ltd. 2008 Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. Insulin Resistance (dpeaa)DE-He213 Metabolic Syndrome (dpeaa)DE-He213 Structural Equation Modelling (dpeaa)DE-He213 Oral Glucose Tolerance Test (dpeaa)DE-He213 Physiological Variable (dpeaa)DE-He213 Linneberg, Allan aut Werge, Thomas aut Jørgensen, Torben aut Enthalten in BMC genetics London : BioMed Central, 2000 9(2008), 1 vom: 08. Juli (DE-627)326644938 (DE-600)2041497-3 1471-2156 nnns volume:9 year:2008 number:1 day:08 month:07 https://dx.doi.org/10.1186/1471-2156-9-43 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2008 1 08 07
language	English
source	Enthalten in BMC genetics 9(2008), 1 vom: 08. Juli volume:9 year:2008 number:1 day:08 month:07
sourceStr	Enthalten in BMC genetics 9(2008), 1 vom: 08. Juli volume:9 year:2008 number:1 day:08 month:07
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Insulin Resistance Metabolic Syndrome Structural Equation Modelling Oral Glucose Tolerance Test Physiological Variable
isfreeaccess_bool	true
container_title	BMC genetics
authorswithroles_txt_mv	Fenger, Mogens @@aut@@ Linneberg, Allan @@aut@@ Werge, Thomas @@aut@@ Jørgensen, Torben @@aut@@
publishDateDaySort_date	2008-07-08T00:00:00Z
hierarchy_top_id	326644938
id	SPR027004163
language_de	englisch
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This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. 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author	Fenger, Mogens
spellingShingle	Fenger, Mogens misc Insulin Resistance misc Metabolic Syndrome misc Structural Equation Modelling misc Oral Glucose Tolerance Test misc Physiological Variable Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis
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topic_title	Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis Insulin Resistance (dpeaa)DE-He213 Metabolic Syndrome (dpeaa)DE-He213 Structural Equation Modelling (dpeaa)DE-He213 Oral Glucose Tolerance Test (dpeaa)DE-He213 Physiological Variable (dpeaa)DE-He213
topic	misc Insulin Resistance misc Metabolic Syndrome misc Structural Equation Modelling misc Oral Glucose Tolerance Test misc Physiological Variable
topic_unstemmed	misc Insulin Resistance misc Metabolic Syndrome misc Structural Equation Modelling misc Oral Glucose Tolerance Test misc Physiological Variable
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title	Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis
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title_full	Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis
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author_browse	Fenger, Mogens Linneberg, Allan Werge, Thomas Jørgensen, Torben
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author-letter	Fenger, Mogens
doi_str_mv	10.1186/1471-2156-9-43
title_sort	analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis
title_auth	Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis
abstract	Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. © Fenger et al; licensee BioMed Central Ltd. 2008
abstractGer	Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. © Fenger et al; licensee BioMed Central Ltd. 2008
abstract_unstemmed	Background Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks. Methods In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus. Results The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations. Conclusion The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process. © Fenger et al; licensee BioMed Central Ltd. 2008
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title_short	Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis
url	https://dx.doi.org/10.1186/1471-2156-9-43
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Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis

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