| LR + | LR − | |
|---|---|---|
| Risk markers | ||
| Male sex | 1.2 (male) | 0.8 (female) |
| Regular pesticide exposure | 1.5 | n/a |
| Occupational solvent exposure | 1.5 | n/a |
| Nonuse of caffeine | 1.35 | 0.88 |
| Smoking | ||
| Current smoker | n/a | 0.45 |
| Never smoker | 1.25 | n/a |
| Former smoker | n/a | 0.8 |
| Sibling had PD with age onset < 50 | 7.5 | n/a |
| Any other first degree relative with PD | 2.5 | n/a |
| Known gene mutation | Berg et al. (2015) | n/a |
| Substantia nigra hyperechogenicity | 4.7 | 0.45 |
| Prodromal markers | ||
| Polysomnogram-proven RBD or Positive RBD screen questionnaire with >80% specificity or Probable RBD diagnosed on expert interview (specialist in sleep medicine) | 130 2.3 50 | 0.62 0.76 0.62 |
| Dopaminergic PET/SPECT clearly abnormal (e.g., <65% normal, 2 SD below mean) | 40 | 0.65 |
| Possible subthreshold parkinsonism (UPDRS >3 excluding action tremor) or Abnormal quantitative motor testing | 10 3.5 | 0.7 0.60 |
| Olfactory loss | 4.0 | 0.43 |
| Constipation | 2.2 | 0.80 |
| Excessive daytime somnolence | 2.2 | 0.88 |
| Symptomatic hypotension | 5.2 | 0.80 |
| Severe erectile dysfunction | 2 | 0.90 |
| Urinary dysfunction | 1.9 | 0.90 |
| Depression (± anxiety) | 1.8 | 0.85 |
| 3 | 계산된 LR값이 아래 표의 우측 값보다 크면, 'probable prodromal PD'로 진단됨. | 998 > 515 so he is, 'probable prodromal PD' | ||||||||||||||||||||||||
Table 3 Likelihood Ratio Thresholds for Diagnosis of Prodromal PD
| ||||||||||||||||||||||||||
| 4 |
ONLine calculator에서 posterior probability 얻음. or disease prevalence, positive likelihood ratio, and negative likelihood ratio (and, optionally, sample size):
Optional information http://araw.mede.uic.edu/cgi-bin/testcalc.pl Sample output: 8 Sick / 993 Well | 8 / 0 / 1 / 992 (true positive / false negative / false positive / true negative); posterior-probability nomogram (Prior prob / Likelihood ratio / Posterior prob axes 0.1–99). His probability of having prodromal PD is ~88% | |||||||||||||||||||||||||
Phenoconversion
| In PARS Study ( |
hyposmia + DAT deficit (did not focus on iRBD), , 3. 68% (14/21) converted to PD or DLB (1/21) within 4 years. a. Assumption: 68% 4-year conversion rate suggests conversion rate of ~ 17%/year or about 51% in 3 years | |
| Postuma ~probably {Postuma, 2019 #1731} | (RBD + combination of risk factors): without reliance on DAT — 60% - 65% 3-year conversion rate = 20%/year, | |
| Iranzo: | iRBD, +DAT vs −DAT (no other risk factors) — 3-year phenoconversion rates: 20% vs ... | |
| MJFF PPMI 1.0: | N=38 iRBD + DAT scan +: 14/38 (37%) phenoconverted within 3 years ~12.3%/year (79% PD, 21% DLB) | |
| Takeda suggested: |
only persons with specific combination of risk factors, including + DAT scan:
| |
| {Miglis, 2021 #1732} 2019 MDS abstract Path to Prevention (P2P) – Developing a Prodromal PD Progression Biomarker Program - MDS Abstracts.pdf | review | Data from PPMI and PARS suggests that among subjects identified with either RBD or hyposmia, who have DAT deficit, risk of conversion to motor parkinsonism within 3 years is approximately 30% |
Takeda efforts in prodromal PD
| MNI | PhReT? |
| NCNP | kamiguchi |
| Study title? (w TAK-341) | Rob Rubens |
| NDU Strategy document | including the advent of a CSF biomarker for αSYN (SAA assay) with efforts underway to validate an SAA assay in plasma. We are finding increasing evidence that genetics may predict the rate and nature of pheno-conversion (e.g., GBA, SNCA, TMEM175 variants may affect the rate of conversion). We are currently involved in NeuroGenomics Partnership focusing on rapid eye movement sleep behavior disorder (RBD), in which we hope to identify genetic associations with rate of conversion from RBD to PD. This might help to identify rapid converters and stratify them for enrolment into future clinical trials. |
https://mytakeda-my.sharepoint.com/personal/jae_won_lee_takeda_com/documents/myTakeda
NDM prototype of PD: Takeda is currently working on establishing a partnership with Montreal Neurological Institute (the NeuroGenomics Partnership), to sequence RBD patients to identify genetic associations with rate of conversion from iRBD to PD (or DLB or MSA). GBA occurs in up to 10% of idiopathic RBD (iRBD) cohorts (higher than PD). Another PD gene, TMEM175, is also strongly linked to RBD. A comprehensive genetic analysis in iRBD patients may identify rapid converters and stratify them for enrolment into future clinical trials. Discussions with relevant KOLs such as Ziv Gan-Or may also yield helpful insights.
potential preventive trial design with prodromal PD (presented at 20200915 Clinical Group Meeting)
Endpoint: 3 years; 46% of pbo will phenoconvert (20.5%/y), HR=0.7
Mass screening of N=500,000 persons with questionnaires → 50% (N=250,000) will return → 50% (N=125,000) will meet inclusion criteria
→ N of 100,000 will sign ICF → 15% (N=15,000) will pass UPSIT and iRBD questionnaires → 30% (N=3,840) will pass in-clinic exam (including motor) → N=2,600 will have DATscan deficit + RBD (confirmed PSG)/hyposmia. → N=1,888 will be randomized to treatment groups (TAK-341-HD, TAK-341-LD, pbo) in a 2:1:2 allocation ratio (755:378:755)
Clinical trials in prodromal PD
REVIEW
- {Smedinga, 2021 #1555}
- {Poortvliet, 2020 #1556}
P2P Platform Trial
Protocol (master protocol)
| Inclusion criteria |
|
| Duration of Tx per arm: |
24 m Overall platform trial sample size is based on the number of regimens, with each regimen comparing active treatment versus a shared placebo. For the purposes of sample size planning, we examined regimen sample sizes range from 80 to 250 participants concurrently randomized in a 1:1 manner to active treatment versus shared placebo. Interim analyses are conducted to select a sample size for each regimen according to a prespecified algorithm using Bayesian predictive probabilities. Sample size calculations demonstrate that 225, 125, and 80 participants per regimen on active treatment, compared to an equal number of participants concurrently randomized to shared placebo, are required for 80% power to detect a 30%, 40%, or 50% reduction in slope/progression on DAT imaging endpoint. In the same setting with the MDS-UPDRS endpoint, we can detect a 35% and 35% slope reduction with 225 and 125 active participants per regimen on active treatment, compared to an equal number of participants concurrently randomized to shared placebo. |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| ONLine calculator block | sample input row Total sample size: (empty) | The “Total sample size” input is blank in the source; preserved as empty cell. |
| Posterior nomogram axis labels | Prior prob. / Likelihood ratio / Posterior prob. axes 0.1-99 | The nomogram is rendered as a small embedded image; only the source-printed axis tick labels are transcribed. |
| PARS Phenoconversion conversion rate | ~17%/year | The conversion-rate annotation is hand-derived in the source (“Assumption: 68% 4-year conversion rate suggests…”); the ~17%/year figure is preserved as printed. |