Cigarette Variability (CVAR) Task Force Study Designs, Statistical ...€¦ · Force Study Designs, Statistical Considerations, Initial Observations, and Limitations 2018_IG02_Morton.pdf

Michael Morton, Rana Tayyarah, and Jason Flora

Kunming, China

23 October 2018

Cigarette Variability (CVAR) Task

Force Study Designs, Statistical

Considerations, Initial Observations,

and Limitations

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❖ Cigarette Variability (CVAR) Task Force was formed in 2014

❖ Examining various smoke and filler constituents and select physical

properties

❖ Broken into three separate studies:

➢ Phase 1 – three samples over one week

➢ Phase 2 – four samples over a year

➢ Phase 3 – three samples, one sample in each of three years – preliminary data

are available

❖ The studies included nine products, but some had shipment difficulties

➢ 3R4F and, to a limited extent, 1R6F were also included

CVAR Task Force

CVAR Task Force

2018 Congress, Kunming – 1810242

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❖ Sample-to-sample variation is an estimate of how different one sample is

from another

➢ Variation among the “true” sample means

➢ Inferred from differences in the mean values associated with each sample

➢ With small numbers of samples (3 or 4 in our case), the sample-to-sample

standard deviation will not be well estimated, but we can see illustrative

examples of sample differences

❖ Power to detect differences

➢ 5 replicates per sample gives statistical power to detect sample

differences if sample-to-sample SD is ~1.3 times larger than rep-to-rep SD

Sample-to-sample variation

CVAR Task Force


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❖ To avoid confusing laboratory drift with sample differences, samples

were put into cold storage (−23°C) so that all samples could be analyzed

at the same time

❖ Sample replicates were interleaved to provide additional protection

against lab drift affecting the sample-to-sample comparisons

❖ Filler analyses can give false statistically significant differences

➢ When tobacco filler replicates are subsamples from a single homogenized

sample sampling variability is lost and the criterion for a difference can

become too small

Statistical/Analytical Considerations

CVAR Task Force


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❖ Examined the samples for statistically significant differences using the

analysis of variance

❖ Calculated percent differences: % Range = 100 * (max− min)/average

➢ This aids in determining if statistical differences are meaningfully large

❖ Compared sample-to-sample differences to 3R4F when split and treated

as separate samples

Statistical Analysis

CVAR Task Force


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Results – Ventilation (%)

CVAR Task Force


Product A B1 C B2 D E F Phase 1 Phase 2/1.21

1 40.2 38.1 38.9 38.9 38.5 38.8 37.8 3.4% 1.5%

2 59.2 59.3 56.8 59.2 58.4 55.8 56.3 5.9% 6.7%

3 0.4 0.3 0.4 0.3 0.2 0.6 0.4 0.1% 0.3%

4 26.5 20.1 24.9 21.4 24.5 22.6 27.6 8.4% 6.7%

6 23.4 22.7 23.3 - - - - 0.9% -

7 80.1 79.1 82.9 79.4 83.7 84.1 83.3 20.9% 21.3%

8 16.0 17.1 16.4 16.7 12.0 15.2 13.6 1.3% 4.6%

9 35.0 34.4 34.5 34.1 34.4 35.9 37.3 0.9% 4.1%

3R4F 31.1 - - 30.9 29.3 29.2 30.3 - 2.0%

5.9% 6.5%

Phase 1 Phase 2

Average Relative Ranges

Relative Ranges

Relative Ranges (%) = ((Max-Min)/(100-Avg of all 7 values) x 100. Relative range calculated as a percent of (100 – ventilation).

Note: Relative ranges are adjusted to account for 3 vs 4 data points by dividing Phase 2 ranges by 1.21

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❖ TNCO measured in each laboratory for each product

❖ Differences between labs were generally larger than those between

samples.

Results – Tar, Nicotine, and CO

CVAR Task Force


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❖ TNCO measured in each laboratory for each product

❖ Differences between labs were generally larger than those between

samples.

Results – Tar, Nicotine, and CO

CVAR Task Force


Product 4 ISO Tar (mg/cig) Phase 1

Lab A B1 C Lab Ave.

1 9.40 9.62 9.34 9.45

4 9.67 9.99 9.41 9.69

5 8.80 9.40 9.16 9.12

6 9.50 9.46 9.42 9.46

7 9.90 10.71 9.99 10.20

8 10.75 11.10 10.54 10.80

9 9.68 10.28 9.76 9.91

10 9.24 10.15 9.20 9.53

11 9.89 10.52 9.93 10.11

Ave. 9.65 10.14 9.64 9.81

% Sample Range 5.1%

%Lab Range 17.1%

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Nicotine in Filler (as-is)

Phase 1 – one week Phase 2 – one year

CVAR Task Force


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❖ Filler Nicotine values showed larger differences over 1 year

compared to over 1 week (Percent Relative Ranges)

Filler Nic.


1 13.8 14.1 13.9 13.7 14.3 14.8 15.1 2.1% 8.2%

2 16.6 16.8 16.6 17.3 16.1 15.4 15.1 1.0% 11.2%

3 16.4 15.8 15.6 15.0 14.9 15.4 14.8 4.9% 3.3%

4 15.1 15.4 15.6 15.6 15.5 15.5 15.0 3.1% 3.1%

6 16.4 16.5 16.4 16.7 16.7 15.9 15.9 1.0% 4.2%

7 16.8 17.6 17.2 17.0 17.4 17.9 17.4 4.7% 4.3%

8 18.5 18.4 18.1 18.2 18.8 18.7 18.1 2.1% 3.2%

9 15.5 15.3 15.9 16.0 17.5 16.9 17.2 3.7% 7.3%

3R4F 16.9 16.9 16.9 16.6 16.8 16.9 16.7 0.4% 1.4%

2.8% 5.6%Average Relative Ranges

Phase 1 Phase 2 Relative Ranges

1 week 1 year

CVAR Task Force


Relative Ranges (%) = ((Max-Min)/Avg of all 7 values) x 100 Note: Relative ranges are adjusted to account for 3 vs 4 data points by dividing Phase 2 ranges by 1.21

Filler Nicotine (mg/g) (as-is)

Phase 1 vs. Phase 2

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Nicotine in Filler and smoke – Phase 2

CVAR Task Force


Nicotine in Filler (mg/g)

Product B2 D E F

1 13.65 14.28 14.84 15.07

2 17.31 16.12 15.44 15.11

3 15.01 14.86 15.39 14.77

4 15.61 15.53 15.45 15.04

6 16.72 16.68 15.89 15.88

7 17.02 17.40 17.92 17.35

8 18.23 18.82 18.74 18.10

9 16.00 17.45 16.86 17.15

3R4F 16.59 16.81 16.87 16.67

ISO Nicotine (mg/cig)

Product B2 D E F

1 0.769 0.761 0.814 0.811

2 0.303 0.313 0.313 0.295

3 0.843 0.825 0.837 0.848

4 0.740 0.723 0.749 0.717

6 1.161 1.146 1.207 1.166

7 0.103 0.066 0.056 0.060

8 0.794 0.895 0.775 0.817

9 0.653 0.682 0.658 0.644

3R4F 0.755 0.745 0.757 0.763

❖ There is a rough correspondence between nicotine in filler and nicotine in smoke

➢ Smoke generation has additional noise that weakens the correlation

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NNN in Filler (as-is)

CVAR Task Force


Phase 1 – one week Phase 2 – one year

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❖ Filler NNN values showed greater variability over 1 year

compared to over 1 week

Filler NNN


1 727 726 717 791 1257 1248 1149 1.1% 40.7%

2 774 833 785 739 690 550 765 8.1% 24.2%

3 132 117 128 139 121 112 82 12.6% 40.3%

4 2308 2238 2283 2090 2416 2188 2247 3.1% 12.0%

6 1163 1155 1129 1091 1282 1132 1456 2.8% 25.1%

7 814 870 856 825 750 1059 949 6.3% 29.2%

8 93 105 108 108 107 98 78 15.1% 24.7%

9 571 675 751 671 431 306 383 33.4% 55.7%

3R4F 2817 2712 2742 2690 2767 2712 2754 3.8% 2.3%

10.3% 31.5%



1 week 1 year

CVAR Task Force



Filler NNN (ng/g) (as-is)

Phase 1 vs. Phase 2

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Smoke NNN Phase 2

CVAR Task Force


ISO NNN (ng/cig)

Product B2 D E F

1 45.0 65.4 60.0 50.7

2 14.5 14.9 13.2 14.6

3 6.00 6.36 7.28 5.88

4 91.6 93.8 89.9 88.6

6 68.5 66.0 71.5 71.8

7 7.88 4.80 5.12 4.84

8 4.48 6.16 4.20 3.84

9 27.0 17.8 18.2 19.3

3R4F 113 110 124 106

CI NNN (ng/cig)

Product B2 D E F

1 105 154 159 155

2 61 61 46 53

3 14.1 17.5 13.0 9.1

4 216 219 209 213

6 151 164 142 175

7 82 65 68 71

8 10.7 10.7 9.5 9.3

9 72 55 46 43

3R4F 267 277 268 250

Filler NNN (ng/g)

Product B2 D E F

1 791 1257 1248 1149

2 739 690 550 765

3 139 121 112 82

4 2090 2416 2188 2247

6 1091 1282 1132 1456

7 825 750 1059 949

8 108 107 98 78

9 671 431 306 383

3R4F 2690 2767 2712 2754

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❖ Smoke B[a]P values showed similar variability over 1 year

compared to 1 week

CI B[a]P


1 16.0 16.3 16.4 16.8 17.4 16.8 17.2 2.1% 3.2%

2 6.6 6.6 6.5 6.8 6.8 6.7 6.9 2.8% 3.0%

3 13.1 13.4 13.4 13.1 14.0 13.7 13.7 2.7% 6.0%

4 15.7 15.8 16.0 15.2 14.9 15.3 15.0 2.1% 1.7%

6 10.8 11.0 11.0 11.7 11.5 11.3 11.9 1.8% 4.7%

7 6.5 6.5 6.5 7.0 7.0 6.8 7.0 0.4% 2.2%

8 12.6 13.1 13.0 12.1 12.6 12.4 12.3 3.8% 3.5%

9 10.0 10.3 10.4 10.3 10.3 10.0 10.7 3.1% 6.1%

3R4F 15.0 15.1 15.3 16.2 16.2 15.7 15.3 2.3% 5.2%

2.4% 3.8%



1 week 1 year


CVAR Task Force


CI Smoke B[a]P (ng/cig)

Phase 1 vs. Phase 2

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❖ With a small number of samples per product, variability will not be quantitatively

well estimated, but illustrative examples of differences are possible

❖ Samples were all put into cold storage so that all could be analyzed at the same

time to avoid confusing laboratory shifts with sample differences

❖ In the short-term, generally filler differences and smoke yield differences are

small

❖ In the longer term, tobacco filler and related smoke yield differences are often

larger

❖ Smoke yields of tobacco related constituents broadly follow the filler

concentrations

❖ Combustion related analytes tend to differ less than tobacco related analytes

Summary

CVAR Task Force


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Documents

Cigarette Variability (CVAR) Task Force Study Designs, Statistical ...€¦ · Force Study Designs, Statistical Considerations, Initial Observations, and Limitations 2018_IG02_Morton.pdf