- PPMI measurement: {Bartl, 2021 #2736}
| {Bartl, #2736} | 2021 | chromophore |
Longitudinal cerebrospinal fluid (CSF) samples from PPMI (252 PD, 115 healthy controls, HC) were analyzed at six timepoints (baseline, 6, 12, 24, 36, and 48 months follow-up) αSyn was significantly lower in PD (mean 103 pg/ml vs. HC: 127 pg/ml, p<0.01; area under the curve [AUC]: 0.64), while all other biomarkers were not significantly different (AUC NfL: 0.49, sTREM2: 0.54, YKL40: 0.57, GFAP: 0.55, IL-6: 0.53, S100: 0.54, p>0.05) and none showed a significant difference longitudinally. |
Below LOD data
Strategies for handling data below LOD in data analysis (https://olink.com/faq/how-is-the-limit-of-detection-lod-estimated-and-handled/)
Several strategies exist for handling data below LOD that varies in complexity. Olink delivers data below LOD to allow researches to choose the strategy that is best for their study and interpret results with the complexity of data below LOD in mind. Some examples of strategies include:
- Use actual data below LOD: As data below LOD may be non-linear this data should be interpreted cautiously. However, especially in large multiplate studies LOD is a conservative measurement. Using actual data may increase the statistical power and gives a more normal distribution of the data. Including data under LOD does commonly not increase false positives as there is generally no significant difference between groups under LOD (values tend to be condensed to a very small range).
- Replace data below LOD: Data values below the LOD may be replaced with a fixed value, commonly the LOD. This will truncate the lower end of the data distribution rendering a less normal distribution. Estimates of e.g. the mean will be biased and parametric statistical tests may have lower statistical power.
- Impute data below LOD: A more complex approach for handling data below LOD is to impute the true value. There exist various approaches for imputation of data below LOD.
[PK]
Parameters
| AUC |
my clin pharm colleague Michelle Jia provided the following information about AUC tau: AUC24 and AUCtau are both AUC from 0 to 24 hours, in a QD dosing regimen. The difference is sometimes not very clear. Some people think AUC24 is Day 1 or on any Day from 0 to 24. Some people think AUCtau is at steady state, but AUCtau can also mean AUC24 on Day 7 or Day 14. To be more precise, we use AUCtau,ss to represent at steady state. In this case, AUC24,ss is as same as AUCtau,ss. |
Dose-PK-PD-Efficacy relationship in Vivo
(Farrell et al. 2019, PMID 31537613)
핵심은 short term 으로 long term 을 예측하는 것!
| Dose | PK | PD | Efficacy | ||
|---|---|---|---|---|---|
| 단기 TE | 장기 | ||||
| Drug Plasma concentration | Drug concentration in target tissue | Substrate level in target tissue | |||
| 1. PK-PD-E: single | |||||
| NMet14-3-3 in Fat tissue | Wt loss (%) | ||||
| 3 mg/kg | 1000 ng/ml | 3 | 2 | ||
| 10 mg/kg | 5000 ng/ml | 5 | 3 | ||
| 30 mg/kg | 12,000 ng/ml | 8 | 8 | ||
| 2. PK-PD-E: Chronic | |||||
| Dose | Single (actual) | Single (actual) PBMC (b/c fat tissue and PBMC produced similar TE) | |||
| dose | Chronic (SS) (simulated) fig 4D, PBMC | Chronic (actual) [Panel C: BAT PD vs scWAT PD plotted against PD: NMet14-3-3γ/GAPDH (x-axis 0–14) with E: % Body Weight Loss on y-axis (0–14); arms labelled 3 mg/kg, 10 mg/kg, 30 mg/kg. Caption: [Dose-(Chronic) PD- Chronic efficacy].] | |||
| Acetyl-tubulin | Tau reduction | ||||
Questions
| the data from a single-dose PD study could be used to predict longer-term efficacy?, |
핵심그림(좌, 우 변수가 다 translationabl 해야함!)! [Dose-single dose PD- Chronic efficacy] □: efficacy (Left), ▪: TE PD (Right), [Panel A: Target Engagement PD and BWL Efficacy versus Dose; y-axis %BWL Efficacy@14day (0–25), x-axis Dose (mg/kg) on log scale 1–100; two series, solid line with filled circles (BWL Efficacy) and dashed line with open squares (Simulated Target Engagement PD).] |
해석) - 1–3 mg/kg애기: the AUE for TE increased approx. 2.5-fold; however, this dose was not sufficient to cause BWL, - (10 mg/kg애기구나), an efficacy of 5% BWL correlates with an approx. 5-fold increase in TE, 즉 minimum TE needed for Efficacy는 5 구나, - (15 mg/kg애기). an efficacy of 10% BWL correlates with an approx. 10-fold increase in TE |
| What is the minimum TE needed for Efficacy? |
(Translationable) PD ←——→ (Translationable) Efficacy [Empty axis box labelled exposure on the x-axis between the two (Translationable) labels.] 결국 위의 그림 필요! | |
| Is there a correlation between (Simulated) TE (in PBMC) and efficacy (in mice)? (Can TE be used to predict Efficacy?) | [Panel B: BWL Efficacy versus Simulated Target Engagement PD; y-axis %BWL Efficacy@14day; R²=0.9577 visible at top of panel. Panel is partially cropped at the bottom of the photo.] | |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Top NTK assays table tail | (rows for ABK42 / AB40 / sTau / NfL / sTREM2 / YKL40 on the pink left half and IL-6 / S100b / GFAP / GDF-15 / IGFBP7 / NSE / pTau 181 / APOE4 on the pink right half) | The table header and earlier rows are above this capture; column structure for sample volumes (10–50 µL) and assay tags (e411 / e601) is preserved as evidence only. |
| PK-PD-E Chronic ‘Dose’ row middle column | (empty) | The ‘Drug concentration in target tissue’ column is empty in the chronic block of the source. |
| Panel B (bottom) | (BWL Efficacy versus Simulated Target Engagement PD scatter) | Bottom of the chart is cut at -25 on the y-axis; the remaining axis labels and data points continue on 20240722_184720. |
15 mg/kg애기 interpretation bullet | (15mg/kg애기). an efficacy of 10% BWL correlates with an approx. 10-fold increase in TE | The third bullet repeats 15 mg/kg but is preceded by a 10 mg/kg bullet; both are preserved as printed. |