Predictive Accuracy of a Clinical Model for Carriage of Pathogenic/Likely Pathogenic Variants in Patients with Dementia and a Positive Family History at PUMCH
<b>Background and Objectives:</b> Identifying carriers of Pathogenic/Likely Pathogenic Variants in patients with dementia is crucial for risk stratification, particularly in individuals with a family history. This study developed and validated a clinical prediction model using whole-exom...
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2025-05-01
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| author | Jialu Bao Yuyue Qiu Tianyi Wang Li Shang Shanshan Chu Wei Jin Wenjun Wang Yuhan Jiang Bo Li Yixuan Huang Bo Hou Longze Sha Yunfan You Yuanheng Li Meiqi Wu Yutong Zou Yifei Wang Li Huo Ling Qiu Qi Xu Feng Feng Chenhui Mao Liling Dong Jing Gao |
| author_facet | Jialu Bao Yuyue Qiu Tianyi Wang Li Shang Shanshan Chu Wei Jin Wenjun Wang Yuhan Jiang Bo Li Yixuan Huang Bo Hou Longze Sha Yunfan You Yuanheng Li Meiqi Wu Yutong Zou Yifei Wang Li Huo Ling Qiu Qi Xu Feng Feng Chenhui Mao Liling Dong Jing Gao |
| author_sort | Jialu Bao |
| collection | DOAJ |
| description | <b>Background and Objectives:</b> Identifying carriers of Pathogenic/Likely Pathogenic Variants in patients with dementia is crucial for risk stratification, particularly in individuals with a family history. This study developed and validated a clinical prediction model using whole-exome sequencing-confirmed cohorts. <b>Methods:</b> A total of 601 Chinese patients with dementia and a family history were enrolled at Peking Union Medical College Hospital, with 476 in a retrospective derivation cohort and 125 in a temporal validation cohort. Predictive factors included age at onset, <i>APOE</i> ε4 status, and family history characteristics. Model performance was assessed using discrimination and calibration metrics. <b>Results:</b> In the derivation cohort (median age at onset 66 years), 10.3% carried Pathogenic/Likely Pathogenic Variants. Among patients with dementia, those with age at onset < 55 years (OR 2.56, <i>p</i> = 0.0098), more than two affected relatives (OR 3.32, <i>p</i> = 0.0039), parental disease history (OR 4.72, <i>p</i> = 0.015), and early-onset cases in the family (OR 2.61, <i>p</i> = 0.0096) were positively associated with Pathogenic/Likely Pathogenic Variant carriage, whereas <i>APOE</i> ε4 carriage was inversely associated (OR 0.36, <i>p</i> = 0.0041). The model achieved an area under the curve of 0.776 (95% CI, 0.701–0.853) in the derivation cohort and 0.781 (95% CI, 0.647–0.914) in the validation cohort (median age at onset 58 years), with adequate calibration. <b>Conclusions:</b> This model demonstrated strong predictive performance for Pathogenic/Likely Pathogenic Variant carriage, supporting its clinical utility in guiding genetic testing. Further research is needed to refine the model. |
| format | Article |
| id | doaj-art-af4a8dfcc5be40e8818258ce9ff04c08 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-af4a8dfcc5be40e8818258ce9ff04c082025-08-20T03:47:49ZengMDPI AGBiomedicines2227-90592025-05-01135123510.3390/biomedicines13051235Predictive Accuracy of a Clinical Model for Carriage of Pathogenic/Likely Pathogenic Variants in Patients with Dementia and a Positive Family History at PUMCHJialu Bao0Yuyue Qiu1Tianyi Wang2Li Shang3Shanshan Chu4Wei Jin5Wenjun Wang6Yuhan Jiang7Bo Li8Yixuan Huang9Bo Hou10Longze Sha11Yunfan You12Yuanheng Li13Meiqi Wu14Yutong Zou15Yifei Wang16Li Huo17Ling Qiu18Qi Xu19Feng Feng20Chenhui Mao21Liling Dong22Jing Gao23State Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaDepartment of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, ChinaState Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Nuclear Medicine, Center for Rare Diseases Research Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, ChinaDepartment of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, ChinaDepartment of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Nuclear Medicine, Center for Rare Diseases Research Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, ChinaDepartment of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, ChinaState Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100730, ChinaDepartment of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, ChinaState Key Laboratory of Complex Severe and Rare Diseases, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital Translational Medical Center, Beijing 100730, China<b>Background and Objectives:</b> Identifying carriers of Pathogenic/Likely Pathogenic Variants in patients with dementia is crucial for risk stratification, particularly in individuals with a family history. This study developed and validated a clinical prediction model using whole-exome sequencing-confirmed cohorts. <b>Methods:</b> A total of 601 Chinese patients with dementia and a family history were enrolled at Peking Union Medical College Hospital, with 476 in a retrospective derivation cohort and 125 in a temporal validation cohort. Predictive factors included age at onset, <i>APOE</i> ε4 status, and family history characteristics. Model performance was assessed using discrimination and calibration metrics. <b>Results:</b> In the derivation cohort (median age at onset 66 years), 10.3% carried Pathogenic/Likely Pathogenic Variants. Among patients with dementia, those with age at onset < 55 years (OR 2.56, <i>p</i> = 0.0098), more than two affected relatives (OR 3.32, <i>p</i> = 0.0039), parental disease history (OR 4.72, <i>p</i> = 0.015), and early-onset cases in the family (OR 2.61, <i>p</i> = 0.0096) were positively associated with Pathogenic/Likely Pathogenic Variant carriage, whereas <i>APOE</i> ε4 carriage was inversely associated (OR 0.36, <i>p</i> = 0.0041). The model achieved an area under the curve of 0.776 (95% CI, 0.701–0.853) in the derivation cohort and 0.781 (95% CI, 0.647–0.914) in the validation cohort (median age at onset 58 years), with adequate calibration. <b>Conclusions:</b> This model demonstrated strong predictive performance for Pathogenic/Likely Pathogenic Variant carriage, supporting its clinical utility in guiding genetic testing. Further research is needed to refine the model.https://www.mdpi.com/2227-9059/13/5/1235dementiafamily historyage at onsetwhole exome sequencing<i>APOE</i> εclinical prediction model |
| spellingShingle | Jialu Bao Yuyue Qiu Tianyi Wang Li Shang Shanshan Chu Wei Jin Wenjun Wang Yuhan Jiang Bo Li Yixuan Huang Bo Hou Longze Sha Yunfan You Yuanheng Li Meiqi Wu Yutong Zou Yifei Wang Li Huo Ling Qiu Qi Xu Feng Feng Chenhui Mao Liling Dong Jing Gao Predictive Accuracy of a Clinical Model for Carriage of Pathogenic/Likely Pathogenic Variants in Patients with Dementia and a Positive Family History at PUMCH Biomedicines dementia family history age at onset whole exome sequencing <i>APOE</i> ε clinical prediction model |
| title | Predictive Accuracy of a Clinical Model for Carriage of Pathogenic/Likely Pathogenic Variants in Patients with Dementia and a Positive Family History at PUMCH |
| title_full | Predictive Accuracy of a Clinical Model for Carriage of Pathogenic/Likely Pathogenic Variants in Patients with Dementia and a Positive Family History at PUMCH |
| title_fullStr | Predictive Accuracy of a Clinical Model for Carriage of Pathogenic/Likely Pathogenic Variants in Patients with Dementia and a Positive Family History at PUMCH |
| title_full_unstemmed | Predictive Accuracy of a Clinical Model for Carriage of Pathogenic/Likely Pathogenic Variants in Patients with Dementia and a Positive Family History at PUMCH |
| title_short | Predictive Accuracy of a Clinical Model for Carriage of Pathogenic/Likely Pathogenic Variants in Patients with Dementia and a Positive Family History at PUMCH |
| title_sort | predictive accuracy of a clinical model for carriage of pathogenic likely pathogenic variants in patients with dementia and a positive family history at pumch |
| topic | dementia family history age at onset whole exome sequencing <i>APOE</i> ε clinical prediction model |
| url | https://www.mdpi.com/2227-9059/13/5/1235 |
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