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Transcript of M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research...
![Page 1: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/1.jpg)
M.Res Programme
CRITICAL APPRAISAL
Bob Lightowlers, WT Centre for Mitochondrial Research
![Page 2: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/2.jpg)
NOT EVERYTHING THAT IS PUBLISHED IS CORRECT!!
![Page 3: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/3.jpg)
NOT EVERYTHING THAT IS PUBLISHED IS CORRECT!!
‘The statistical error that keeps on coming’
Ben Goldacre – The Guardian 9th Sept 2011
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• Numbers of mice not likely to generate significance• No randomisation• No blinded evaluations • Bias in reporting (no reporting of negative data)• Variable genetic background
• Broader endpoints such as life expectancy/behaviour too crude
Problem transferring ‘effective’drugs from mouse model toclinic
Nonhuman primate models ?
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Sept 2011 Bayer Pharmaceuticals assessed reproducibility of 67 published projects
Only 20-25% of published data in line with in-house findings
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Jan 2012Amgen tried to confirm research from 53 published ‘landmark’ studies
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Jan 2012Amgen tried to confirm research from 53 published ‘landmark’ studies
ONLY 6 (11%) could be confirmed
![Page 10: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/10.jpg)
Jan 2012Amgen tried to confirm research from 53 published ‘landmark’ studies
ONLY 6 (11%) could be confirmed
![Page 11: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/11.jpg)
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What causes this lack of reproducibility ?
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What causes this lack of reproducibility ?
![Page 14: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/14.jpg)
What causes this lack of reproducibility ?
![Page 15: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/15.jpg)
What causes this lack of reproducibility ?
![Page 16: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/16.jpg)
What causes this lack of reproducibility ?
![Page 17: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/17.jpg)
NOT EVERYTHING THAT IS PUBLISHED IS CORRECT!!
ONLY 15% OF PUBLICATIONS ARE TRUSTWORTHY
• Be critical
• Guilty until proven innocent
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The peer review process
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What should we be looking for ?
• Incorrect statistical analysis• Power of study• Absence of essential controls• Incorrect methodology• Over/mis interpretation of data• Lack of reference to any conflicting data
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What should we be looking for ?
• Incorrect statistical analysis• Power of study• Absence of essential controls• Incorrect methodology• Over/mis interpretation of data• Lack of reference to any conflicting data
• Falsification of data
![Page 21: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/21.jpg)
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Somatic Cell Nuclear Transfer
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Peer review cannot guarantee scientific integrity
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Peer review cannot guarantee scientific integrity
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http://www.biochem.arizona.edu/classes/bioc568/papers.htm
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Critical Evaluation - a worked example
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Human mtDNA
• An autosomally replicating genome
• Found in mitochondrial matrix
• Comprises app. 0.1% of total cell DNA
• Varies enormously in copy number/cell Approx. 700 in fibroblasts to >200,000 in some mammalian oocytes
• Maternally inherited
• Often heteroplasmic in the diseased state
16,569 bp
• Encodes 13 proteins, all of which are OXPHOS components
![Page 33: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/33.jpg)
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Hypothesis:
1. Alzheimers Disease could be caused by defects in activity of the respiratory chain complex cytochrome c oxidase
2. Alzheimers Disease is due to mutations in the mitochondrial genome
![Page 35: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/35.jpg)
Why ?
• Lack of FH is a negative risk factor
![Page 36: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/36.jpg)
Why ?
• Lack of FH is a negative risk factor • Risk of AD increases with affected maternal relative (mtDNA?)
![Page 37: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/37.jpg)
Why ?
• Lack of FH is a negative risk factor • Risk of AD increases with affected maternal relative (mtDNA?)
• Mutations in mtDNA can lead to defective OXPHOS
![Page 38: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/38.jpg)
Why ?
• Lack of FH is a negative risk factor • Risk of AD increases with affected maternal relative (mtDNA?)
• Mutations in mtDNA can lead to defective OXPHOS
• Neurons may be particularly susceptible to such defects
![Page 39: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/39.jpg)
DiabetesThyroid Disease
Myopathy
Peripheral Neuropathy
Deafness
CVA / Seizures /
Developmental delay
Respiratory Failure Optic Atrophy / Retinitis Pigmentosa
Cardiomyopathy
Short StatureMarrow Failure
Liver Failure
NeurologicalNon-Neurological
![Page 40: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/40.jpg)
Why ?
• Lack of FH is a negative risk factor• • Risk of AD increases with affected maternal relative (mtDNA?)
• Mutations in mtDNA can lead to defective OXPHOS
• Neurons may be particularly susceptible to such defects
• COX activity reported to decrease in brain of AD patients
![Page 41: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/41.jpg)
Methods used
• MtDNA isolation and sequencing in patients, asymptomatic relatives and controls
![Page 42: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/42.jpg)
Methods used
• MtDNA isolation and sequencing in patients, asymptomatic relatives and controls
• All three COX genes sequenced
![Page 43: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/43.jpg)
Methods used
• MtDNA isolation and sequencing in patients, asymptomatic relatives and controls
• All three COX genes sequenced
• Platelet fusion from AD patients to neuronal cells lacking mtDNA (rho0)
![Page 44: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/44.jpg)
Generation of transmitochondrialcybrids
Biopsy
EthBr Enucleation
![Page 45: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/45.jpg)
Methods used
• MtDNA isolation and sequencing in patients, asymptomatic relatives and controls
• All three COX genes sequenced
• Platelet fusion from AD patients to neuronal cells lacking mtDNA (rho0)
• Analysis of respiratory enzyme activity in the cybrids
![Page 46: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/46.jpg)
Methods used
• MtDNA isolation and sequencing in patients, asymptomatic relatives and controls
• All three COX genes sequenced
• Platelet fusion from AD patients to neuronal cells lacking mtDNA (rho0)
• Analysis of respiratory enzyme activity in the cybrids
• Analysis of ROS production in cybrids
![Page 47: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/47.jpg)
Results
506 Patients and 95 controls
![Page 48: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/48.jpg)
Results
506 Patients and 95 controls
10 clones of all three COX genes sequence
![Page 49: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/49.jpg)
Results
506 Patients and 95 controls
10 clones of all three COX genes sequence
6 mutations found in COI and COII
![Page 50: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/50.jpg)
Results
506 Patients and 95 controls
10 clones of all three COX genes sequence
6 mutations found in COI and COII
Different levels of heteroplasmy but levels significantly greater in the AD cohort
![Page 51: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/51.jpg)
![Page 52: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/52.jpg)
Results
506 Patients and 95 controls
10 clones of all three COX genes sequence
6 mutations found in COI and COII
Different levels of heteroplasmy but levels significantly greater in the AD cohort
No disease-associated mutations in COIII gene
![Page 53: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/53.jpg)
Results
506 Patients and 95 controls
10 clones of all three COX genes sequence
6 mutations found in COI and COII
Different levels of heteroplasmy but levels significantly greater in the AD cohort
No disease-associated mutations in COIII gene
AD cybrids but not controls had low COX activity
![Page 54: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/54.jpg)
![Page 55: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/55.jpg)
Results
506 Patients and 95 controls
10 clones of all three COX genes sequence
6 mutations found in COI and COII
Different levels of heteroplasmy but levels significantly greater in the AD cohort
No disease-associated mutations in COIII gene
AD cybrids but not controls had low COX activity
Increased production of ROS in AD cybrids
![Page 56: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/56.jpg)
![Page 57: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/57.jpg)
Critical evaluation:
How appropriate and robust are the methods ?
Is the data and evaluation robust ?
Are the conclusions valid, based on the reported data ?
Has the paper been validated by other labs and do the authors self-cite excessively ?
How does the paper stand the test of time ?
Is there any conflict of interest ?
![Page 58: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/58.jpg)
Why has this not been reported before ?
mtDNA is destroyed by boiling
We’re looking at pseudogenes!
![Page 59: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/59.jpg)
How can an apparent increase in nuclear pseudogene mutationspredispose to Alzheimers Disease and cause respiratory chaindeficiency in transmitochondrial cybrids ?
![Page 60: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/60.jpg)
Critical evaluation:
How appropriate and robust are the methods ?
Is the data and evaluation robust ?
Are the conclusions valid, based on the reported data ?
Has the paper been validated by other labs and do the authors self-cite excessively ?
How does the paper stand the test of time ?
Is there any conflict of interest ?
![Page 61: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/61.jpg)
How can an apparent increase in nuclear pseudogene mutationspredispose to Alzheimers Disease and cause respiratory chaindeficiency in transmitochondrial cybrids ?
![Page 62: M.Res Programme CRITICAL APPRAISAL Bob Lightowlers, WT Centre for Mitochondrial Research robert.lightowlers@ncl.ac.uk.](https://reader034.fdocuments.in/reader034/viewer/2022050714/56649cef5503460f949bd153/html5/thumbnails/62.jpg)