Beyond the Age-Period-Cohort Model: the impact of influenza onLexis mortality surfaces.

Jim Oeppen

jeo1@cam.ac.uk

Cambridge Group for the History of Population

Max Planck Institute for Demographic Research

Workshop on Lee-Carter Methods, Edinburgh, September 2004.

Haemagglutinin

HA

Neuraminidase

NA

Influenza Virus

Viral RNA:

Redrawn from Collier and Oxford (1993)

N1H1

8 genes

Antigenic Shift: gene reassortment

Cell

Redrawn from Collier and Oxford (1993)

H1N1

H2N2

Antigenic Shift: gene reassortment

Antigenic Drift: minor mutatations

progressive and cumulative

e.g. A/Wuhan/359/1995 (H3N2)

to A/Sydney/5/1997 (H3N2)

e.g. H1N1 replaced by H2N2

Age Effects and Influenza

2) “Response” side hypotheses:

a) “Frailty” rises with age, and other medical conditions.

b) Intrinsic immunity from mother? (under 6 months?).

1) No “input side” hypotheses.

Age

1.0

Relative Mortality Risk

0

Age-Specific Response to

Antigenic Shift in Influenza

Period Effects and Influenza

4) Immunity is Specific to an Influenza Sub-Type.

3) The new Sub-Type eliminates the old one.

1) Antigenic-Drift produces new variants

2) Antigenic-Shift produces new Sub-Types

5) Virus re-cycling.

Table of shifts.

Identify laboratory versus sero-archaeology

1820 1840 1860 1880 1900 1920 1940 1960 1980 20000

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

Antigenic Shifts in Influenza and Mortality by Age, Period and Cohort

H1N1 H3N2&H1N1H2N2H3N2

Cohort Effects and Influenza

1) “Original Antigenic Sin”

2) Debility and Selection

Complications: Pregnancy

Cardiovascular

Respiratory

Neurological

1917 1918 1919 1920

Birth Cohort

0

20

40

60

80

100

120

Bir

ths

60

80

100

120

140

160

180

200

220

240

260

280

300

Tot

al D

eath

s (x

1000

)

Northern USASouthern USAInfluenza Deaths

Birth Cohorts of Deaf Children and Influenza Deaths

1820 1840 1860 1880 1900 1920 1940 1960 1980 20000

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

Antigenic Shifts in Influenza and Mortality by Age, Period and Cohort

H1N1 H3N2&H1N1H2N2H3N2

Period

Age

100

1841

0

2000

Mortality SurfaceAPC model: Age-Period-Cohort

Cohorts

Age = Period - Cohort

Epidemic:

Period Effect

“Normal Years”

Age

100

1841

0

2000

2.6

Excess Mortality Ratio

2.6

1880

Birth Cohort

Cohort-Period Interaction Effects

?? H1H?

Excess

Mortality

Ratio

1.0

Antigenic Shift

19181848

Epidemic

1891

1880 1900 1920 1940 1960 1980 20000

1

2

3

4

5

Exc

ess

Mor

tali

ty R

atio

Excess Mortality in Influenza Epidemics: Influenza Deaths

Pandemics1968

England & Wales

1880 1900 1920 1940 1960 1980 20000

1

2

3

4

5

Exc

ess

Mor

tali

ty R

atio

Excess Mortality in Influenza Epidemics: Influenza Deaths

Pandemics19681969

England & Wales

1880 1900 1920 1940 1960 1980 20000.96

0.98

1.00

1.02

1.04

1.06

1.08

Exc

ess

Mor

tali

ty R

atio

Excess Mortality in Influenza Epidemics: All Deaths

Pandemics19681969

Pooled HMD data

1820 1840 1860 1880 1900 1920 1940 1960 1980 20000.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

Exc

ess

Mor

tali

ty R

atio

Excess Mortality in Influenza Epidemics: All Deaths

PandemicsHMD pooled 1918

1820 1840 1860 1880 1900 1920 1940 1960 1980 20001

10

100

1000

1

10

100

1000

Rat

e p

er M

illi

onAntigenic Shifts and Influenza Mortality Rate: England and Wales

H3H1? H1 H2H3 H1/H3

1820 1840 1860 1880 1900 1920 1940 1960 1980 20001

10

100

1000

1

10

100

1000

Rat

e p

er M

illi

onAntigenic Shifts and Influenza Mortality Rate: England and Wales

H3H1? H1 H2H3 H1/H3

Berlin

1840 1850 1860 1870 1880 1890 1900 1910

Birth Cohort

100

101

102

103

2

3

456

8

2

3

4567

2

3

4567

Mor

tali

ty R

ate

0

10

20

30

40

50

60

70

80

90

100

Per

cen

tage

wit

h A

nti

bod

ies

Influenza A Antibodies in 1968/9 and Period Influenza Mortality

Eng. & Wales MortalityA/Hong Kong/68 in US citizensA/England/72A/Dunedin/73

1840 1860 1880 1900 1920 1940 1960 1980 20000

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

Antigenic Shifts in Influenza and Mortality by Age, Period and Cohort

H1N1 H3N2&H1N1H2N2H3N2

H3, H3

H3, H1

H1, H1

Log(mortality) = f(Age, Period, Cohort, HN(Cohort)*HN(Period))

H3?H1?

Factor F P-value

Age x Country 2557 <.0001

Period x Country 173 <.0001

Cohort x Country 235 <.0001

APC Model: Sweden + England & Wales: Type III SS

Factor F P-value

Age x Country 1937 <.0001

Period x Country 76 <.0001

Cohort x Country 63 <.0001

HN(cohort) x HN(period) 220 <.0001

1830 1840 1850 1860 1870 1880 1890 1900 1910 1920

Birth Cohort

0

100

200

300

400

500

600

700

800

900

1000

Rat

e pe

r 10

001918 Influenza Morbidity Rate: Cambridge University