10,000 days of drugs: effect of acetylcholinesterase ... · 10,000 days of drugs: e ect of...
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10,000 days of drugs: Effect of Acetylcholinesteraseinhibitors in real-world data
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-HunKim and Pathfinder team
February 2019
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 1 / 19
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Introduction
Alzheimer’s dementia research
Two types of drugs have been licensed for the treatment of AD symptoms:
AcEIs (donepezil, rivastigmine, and galantimine) and NMDA receptorantagonist (memantine) (Jindra et al., 2018)
There is evidence of beneficial effect for all these drugs (Farrimond et al., 2012)
Clinical relevance of these drugs is still controversial, due to the smalleffect sizes (Tan et al., 2014)
Clinical trials have good efficacy and internal validity, but theyunderperform on measures of external validity
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 2 / 19
![Page 3: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/3.jpg)
Introduction
Alzheimer’s dementia research
Two types of drugs have been licensed for the treatment of AD symptoms:
AcEIs (donepezil, rivastigmine, and galantimine) and NMDA receptorantagonist (memantine) (Jindra et al., 2018)
There is evidence of beneficial effect for all these drugs (Farrimond et al., 2012)
Clinical relevance of these drugs is still controversial, due to the smalleffect sizes (Tan et al., 2014)
Clinical trials have good efficacy and internal validity, but theyunderperform on measures of external validity
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 2 / 19
![Page 4: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/4.jpg)
Introduction
Alzheimer’s dementia research
Two types of drugs have been licensed for the treatment of AD symptoms:
AcEIs (donepezil, rivastigmine, and galantimine) and NMDA receptorantagonist (memantine) (Jindra et al., 2018)
There is evidence of beneficial effect for all these drugs (Farrimond et al., 2012)
Clinical relevance of these drugs is still controversial, due to the smalleffect sizes (Tan et al., 2014)
Clinical trials have good efficacy and internal validity, but theyunderperform on measures of external validity
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 2 / 19
![Page 5: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/5.jpg)
Introduction
Alzheimer’s dementia research
Two types of drugs have been licensed for the treatment of AD symptoms:
AcEIs (donepezil, rivastigmine, and galantimine) and NMDA receptorantagonist (memantine) (Jindra et al., 2018)
There is evidence of beneficial effect for all these drugs (Farrimond et al., 2012)
Clinical relevance of these drugs is still controversial, due to the smalleffect sizes (Tan et al., 2014)
Clinical trials have good efficacy and internal validity, but theyunderperform on measures of external validity
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 2 / 19
![Page 6: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/6.jpg)
Introduction
Sources of additional evidence: EHRs
UK-CRIS (Clinical Record Interactive Search)
De-identified information from the secondary care services
Information on primary care service through attachments
Data of interest is locked in natural text format
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 3 / 19
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Introduction
Sources of additional evidence: EHRs
UK-CRIS (Clinical Record Interactive Search)
De-identified information from the secondary care services
Information on primary care service through attachments
Data of interest is locked in natural text format
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 3 / 19
![Page 8: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/8.jpg)
Introduction
Sources of additional evidence: EHRs
UK-CRIS (Clinical Record Interactive Search)
De-identified information from the secondary care services
Information on primary care service through attachments
Data of interest is locked in natural text format
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 3 / 19
![Page 9: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/9.jpg)
Introduction
The goal
1) NLP models that can extract information of interest from the records
2) Epidemiological analysis on the extracted data
3) Investigate personalised therapies based on the available medical historyin UK-CRIS
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 4 / 19
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Introduction
The goal
1) NLP models that can extract information of interest from the records
2) Epidemiological analysis on the extracted data
3) Investigate personalised therapies based on the available medical historyin UK-CRIS
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 4 / 19
![Page 11: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/11.jpg)
New Mind
New Mind 1
Feasibility study:diagnosis of dementia3 drugs (Rivastigmine, Donepezil and Galantamine)2 mental health scores (MMSE and MOCA)
Oxford UK-CRIS Health centre
Rule-based natural language processing model
The algorithms obtained F1 accuracies ranging from 81 to 98%
Epidemiological analysis to investigate deterioration of cognitiveperformance and effect of the drugs
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 5 / 19
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New Mind
New Mind 1
Feasibility study:diagnosis of dementia3 drugs (Rivastigmine, Donepezil and Galantamine)2 mental health scores (MMSE and MOCA)
Oxford UK-CRIS Health centre
Rule-based natural language processing model
The algorithms obtained F1 accuracies ranging from 81 to 98%
Epidemiological analysis to investigate deterioration of cognitiveperformance and effect of the drugs
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 5 / 19
![Page 13: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/13.jpg)
New Mind
New Mind 1
Feasibility study:diagnosis of dementia3 drugs (Rivastigmine, Donepezil and Galantamine)2 mental health scores (MMSE and MOCA)
Oxford UK-CRIS Health centre
Rule-based natural language processing model
The algorithms obtained F1 accuracies ranging from 81 to 98%
Epidemiological analysis to investigate deterioration of cognitiveperformance and effect of the drugs
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 5 / 19
![Page 14: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/14.jpg)
New Mind
New Mind 1
Feasibility study:diagnosis of dementia3 drugs (Rivastigmine, Donepezil and Galantamine)2 mental health scores (MMSE and MOCA)
Oxford UK-CRIS Health centre
Rule-based natural language processing model
The algorithms obtained F1 accuracies ranging from 81 to 98%
Epidemiological analysis to investigate deterioration of cognitiveperformance and effect of the drugs
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 5 / 19
![Page 15: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/15.jpg)
Data
Extracted data
Scale: 11298 for 4,521 patients
MMSE MOCA
6,931 4,367
Medication: 32,760 for 3,577 patients
AChEi Donepezil Galantamine Mementine Rivastigmine
1,981 18,341 1,656 7,068 3,714
Diagnosis: 35,010 for 5,740 patients
AD DLB FTD Mixed Other PPD Unspecified VaD
10,723 937 479 600 4 120 18,918 3,229
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 6 / 19
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Data
Extracted data
Scale: 11298 for 4,521 patients
MMSE MOCA
6,931 4,367
Medication: 32,760 for 3,577 patients
AChEi Donepezil Galantamine Mementine Rivastigmine
1,981 18,341 1,656 7,068 3,714
Diagnosis: 35,010 for 5,740 patients
AD DLB FTD Mixed Other PPD Unspecified VaD
10,723 937 479 600 4 120 18,918 3,229
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 6 / 19
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Data
Extracted data
Scale: 11298 for 4,521 patients
MMSE MOCA
6,931 4,367
Medication: 32,760 for 3,577 patients
AChEi Donepezil Galantamine Mementine Rivastigmine
1,981 18,341 1,656 7,068 3,714
Diagnosis: 35,010 for 5,740 patients
AD DLB FTD Mixed Other PPD Unspecified VaD
10,723 937 479 600 4 120 18,918 3,229
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 6 / 19
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Data
Extraction of the time information
Scale: if date is not extracted take the document date
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Data
Extraction of the time information
Medication: if date is not extracted, use the earliest document date
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 8 / 19
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Data
Extraction of the time information
Diagnosis: use the earliest document date
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 9 / 19
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Data
MMSE across the time of medication
1968 patients with information on scale and medication
1312 with MMSE and 1008 with MOCA scores
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 10 / 19
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Data
Patterns of the data
Number of observations where there is change of drug prescriptions:
No Medication -> AChEi: 877No Medication -> Mementine: 841AChEi -> Mementine: 1098
AChEi -> AChEi: 6463
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 11 / 19
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Method
Generalized additive mixed-effect modelling
Nonlinear and linear structure
1) Proposes optimal relation between variables: y = f (x) + e
The magnitude of cognitive deterioration across time
Periods of significant changes in the slope of the nonlinear functions
2) Linear structure has standard general (multilevel) equation
The participants’ intercept is adjusted in all models
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 12 / 19
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Results
Effect of medication
Period of changes: - 717 to -136 and 197 to NA (11 months ofstabilization)
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 13 / 19
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Results
Effect of medication
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 14 / 19
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Conclusion
New Mind 1 conclusions
Distributions of the health scores, diagnosis and medicine (values and timeinformation) gives evidence towards the overall validity of the extractions
Preserving effect of medication on the negative cognitive changesexperienced by patients (Perera et al., 2014)
Improved precision of the time scale on which we capture effects, however,there is need to improve the extractions of different drugs
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 15 / 19
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Conclusion
New Mind 1 conclusions
Distributions of the health scores, diagnosis and medicine (values and timeinformation) gives evidence towards the overall validity of the extractions
Preserving effect of medication on the negative cognitive changesexperienced by patients (Perera et al., 2014)
Improved precision of the time scale on which we capture effects, however,there is need to improve the extractions of different drugs
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 15 / 19
![Page 28: 10,000 days of drugs: Effect of Acetylcholinesterase ... · 10,000 days of drugs: E ect of Acetylcholinesterase inhibitors in real-world data Nemanja Vaci, Alejo Nevado-Holgado, Andrey](https://reader033.vdocument.in/reader033/viewer/2022060100/60b1cdf7f7945111426c08f8/html5/thumbnails/28.jpg)
Conclusion
New Mind 1 conclusions
Distributions of the health scores, diagnosis and medicine (values and timeinformation) gives evidence towards the overall validity of the extractions
Preserving effect of medication on the negative cognitive changesexperienced by patients (Perera et al., 2014)
Improved precision of the time scale on which we capture effects, however,there is need to improve the extractions of different drugs
Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 15 / 19