Registry based studies and familial recurrence risks

(1)

Registry based studies and

familial recurrence risks

Rolv T. Lie

(2)

Sentrale/lovhjemlede helseregistre i Norge

1. Dødsårsaksregisteret 2. Medisinsk fødselsregister 3. Hjerte- og karregisteret

4. Meldingssystem for smittsomme sykdommer (MSIS) 5. Nasjonalt vaksinasjonsregister

6. Resistensregistrene (NORM, RAVN)

7. Norsk overvåkingssystem for infeksjoner i sykehustjenesten (NOIS) 8. Reseptbasert legemiddelregister

9. Register over svangerskapsavbrudd

10. Kreftregisteret

11. Genetisk masseundersøkelse av nyfødte

12. Norsk pasientregister

13. Informasjonssystem for pleie og omsorgssektoren (IPLOS) 14. Forsvarets helseregister}

Under etablering

1. Helsearkivregisteret

2. System for bivirkningsrapportering

}

(3)

• Helse Nord RHF

• Nordisk register for hidradenitis suppurativa - HISREG

• Norsk Nakke- og Ryggregister

• Nasjonalt kvalitetsregister for ryggkirurgi

• Norsk register for arvelige og medfødte nevromuskulære

• sykdommer

• Norsk register for analinkontinens

• Norsk Register for Gastrokirurgi - NoRGast

• Norsk kvalitetsregister for behandling av spiseforstyrrelser

• - NORSPIS

• Helse Vest RHF

• Norsk kvalitetsregister for artrittsykdommer (NorArtritt)

• Det Norske Nyrebiopsiregisteret

• Nasjonalt register for organspesifikke autoimmune sykdommer

• (ROAS)

• Nasjonalt register for langtids mekanisk ventilasjon (LTMV)

 Nasjonalt register for invasiv kardiologi

 Nasjonalt register for ablasjonsbehandling og elektrofysiologi

• Norsk porfyriregister

• Norsk MS Register og biobank

• Nasjonalt korsbåndregister

• Nasjonalt hoftebruddregister

• Nasjonalt Barnehofteregister

• Nasjonalt register for leddproteser

• Nasjonalt register for kronisk obstruktiv lungesykdom (KOLS)

• Norsk kvalitetsregister for leppe- kjeve- ganespalte

• Norsk Intensivregister (NIR)

• Norsk diabetesregister for voksne

• Norsk kvalitetsregister for fedmekirurgi

• Nasjonalt Kvalitetsregister for Smertebehandling

3

52 nasjonale medisinske kvalitetsregistre (2015

)

› Helse Midt RHF

› Norsk ryggmargsskaderegister - NorSCIR

 Norsk hjertesviktregister

 Norsk hjerneslagregister

 Norsk Karkirurgisk register - NORKAR

 Norsk hjerteinfarktregister

› Helse Sør-Øst RHF

 Nasjonalt register for brystkreft

 Nasjonalt register for føflekkreft

 Nasjonalt register for barnekreft

 Nasjonalt register for gynekologisk kreft

 Nasjonalt register for malignt lymfom og kronisk lymfatisk

 leukemi

 Nasjonalt register for lungekreft

 Nasjonalt register for prostatakreft (NPPC)

 Nasjonalt register for tykk- og endetarmskreft

› Norsk kvinnelig inkontinensregister (NKIR)

› Kvalitetsregister for demens

 Nasjonalt hjertestansregister

 Norsk Pacemaker og ICD-register

› Norsk kvalitetsregister for hiv (NORHIV)

› Norsk gynekologisk endoskopiregister (NGER)

› Norsk Nefrologiregister

 Det norske hjertekirurgiregisteret

› Gastronet

› Nasjonalt kvalitetsregister for døvblindhet

› Nasjonalt traumeregister

› Cerebral pareseregisteret i Norge (CPRN)

› Norsk Nyfødtmedisinsk Kvalitetsregister (NNK)

› Nasjonalt medisinsk kvalitetsregister for barne- og

› ungdomsdiabetes

(4)

Norwegian genealogy data

• IDs of most persons born in Norway since 1953 are registered with the ID of theirs parents in DSF*

• These data may be used to identify families in disease registries

Person-ID ID-mother ID-father

... 08108235732 ... 03045742641 ... 28115434340 ...

...

... 08079032245 ... 03045742641 ... 28115434340 ...

...

... 21071634325 ... 04058245623 ... 08108235732 ...

*The Central Population Registry

(5)

Record linkage 1

... 08108235732 ... 03045742641 ... 28115434340 ...

...

... 08079032245 ... 03045742641 ... 28115434340 ...

...

... 21071634325 ... 04058245623 ... 08108235732 ...

Siblings

(6)

Record linkage 2

... 08108235732 ... 03045742641 ... 28115434340 ...

...

... 08079032245 ... 03045742641 ... 28115434340 ...

...

... 21071634325 ... 04058245623 ... 08108235732 ...

Father-son

(7)

Record linkage 3

... 08108235732 ... 03045741245 ... 28115434340 ...

...

... 08079032245 ... 03045741245 ... 28115434340 ...

...

... 21071634325 ... 04058245623 ... 08108235732 ...

Aunt-nephew

In reality we use pseudonym numbers in stead of real ID-numbers for privacy protection

(8)

Recurrence risks in families are indirect effects

1^st person 2^ndperson

disease D1

disease D2 genes

environment

(9)

Recurrence risks

Absolute risk of recurrence from person 1 to person 2 G_i, genotype of person i

D_i, disease in person i

P(D

₂

| D

₁

)= ∑ P(G

₁

∩ G

₂

) P(D

₂

|G

₂

) P(D

₁

|G

₁

)

G₁,G₂

Relative risk of recurrence (recurrence risk ratio):

RR = P(D

₂

| D

₁

) / P(D

₂

|

^┐

D

₁

)

Some studies use P(D

₂

) as numerator

Genetic relationship Product of penetrances

(10)

Calculation of relative risk of recurrence

A prospective measure of risk used for counselling child’s risk of D given parent had D

RR=

child’s risk of D given parent did not have D Disease D among a relative is treated as exposure just as in other epidemiological studies

Regression models like logistic, log-bionomial and Cox may be used for estimation

Adjustment for confounding is not so relevant (indirect effects) Account for correlated parent-offspring pairs from same family

(11)

Examples of relative risk of recurrence for siblings

Ziegler & König, 2012, Ch. 6

(12)

Consider where we came from

• What were the genetic influences during pregnancy?

• More important for conditions in pregnancy or in children?

• Could still be important for adult disease

(13)

Main (genetic) components of transmission of risk in families

• Maternal genes (m)

• Fetal autosomal genes (f)

• Paternal (f

_p

)

• Maternal (f

_m

)

• Imprinting or POO (f

_p

≠ f

_m

)

• Mitochondrial DNA (M)

• + environment, social, behaviour

Lie, PPE suppl. 2007

(14)

Main genetic components of transmission of risk

m

f

_m

f

_p

M

(15)

Genetic contributions to parent offspring recurrence

Mother-Child Father-Child Genes

Foetal

½ ½

Maternal

½

⁰

Mitochondrial 1 0

(Proportion of genome shared by two individuals)

(16)

Genetic contributions to recurrence

Gjessing&Lie, Statistical Methods in Medical Research, 2008

(Proportion of genome shared by two individuals)

(17)

Questions we could ask from recurrence risks

1. Are fetal (persons own) genes involved?

2. Are POO-effects likely?

3. Are maternal genes (fetal envoronment) involved?

4. Is mitochondrial inheritance involved?

Recurrence risks could tell us where to look for genetic effects

(18)

Tollånes et al. BMJ 2014

Example 1: Recurrence of CP

(19)

Example 2: Pre-eclampsia recurrence

Maternal disease, but only with a pregnancy

(Lie et al. BMJ 1998)

Children are paternal half-sibs:

OR = 1.8 (1.2 – 2.6) (Mostly from f_p)

(20)

Preeklampsia recurrence

(Lie et al. BMJ 1998)

OR = 1.6 (1.01 – 2.9) (Mostly from m and M) OR = 1.8 (0.9 - 2.6)

(Mostly from m) Mothers are paternal half-sibs

Mothers are maternal half-sibs

(21)

Pre-eclampsia recurrence

(Skjærven et al. BMJ 2005)

OR = 1.4 (1.2-1.7)

f

_p

+..

OR = 2.2 (1.9-2.4)

m + f

_m

+ M +..

Through daughter (mother-child):

Through son (father-child):

(22)

…

(23)

Mother-offspring RR=1.5 Father-offspring RR=1.1

Offspring of sisters RR=1.8 Offspring of sister and brother RR=1.1

Mother-offspring RR=1.4 Father-offspring RR=1.2

Offspring of sisters RR=1.6 Paternal half-siblings RR=1.1 Example 3: Preterm birth recurrence

(24)

Boyd HA et al. Am J Epidemiol. 2009

Preterm birth recurrence

(25)

Maternal half-sisters (Identical mitochondria)

RR=1.4

Paternal half-sisters (Unrelated mitochondria)

RR=1.1

Boyd HA et al. Am J Epidemiol. 2009

Preterm birth recurrence

(26)

…

“joint association analysis in mother–infant pairs showed significant associations exclusively with maternal genotypes but not with fetal genotypes, which also indicates a maternal origin of the observed genetic associations”

(27)

(28)

References

Boyd HA, Poulsen G, Wohlfahrt J, Murray JC, Feenstra B, Melbye M. Maternal contributions to preterm delivery.

Am J Epidemiol. 2009 Dec 1;170(11):1358-64.

Gjessing HK, Lie RT. Biometrical modelling in genetics: are complex traits too complex? Stat Methods Med Res.

2008 Feb;17(1):75-96.

Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ. 1998 May 2;316(7141):1343-7.

Lie RT. Intergenerational exchange and perinatal risks: a note on interpretation of generational recurrence risks.

Paediatr Perinat Epidemiol. 2007 Jul;21 Suppl 1:13-8.

Pawitan Y, Reilly M, Nilsson E, Cnattingius S, Lichtenstein P. Estimation of genetic and environmental factors for binary traits using family data. Stat Med. 2004 Feb 15;23(3):449-65.

Skjærven R, Vatten LJ, Wilcox AJ, Rønning T, Irgens LM, Lie RT. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ. 2005 Oct 15;331(7521):877.

Svensson AC, Sandin S, Cnattingius S, Reilly M, Pawitan Y, Hultman CM, Lichtenstein P. Maternal effects for preterm birth: a genetic epidemiologic study of 630,000 families. Am J Epidemiol. 2009 Dec 1;170(11):1365-72.

Tollånes MC, Wilcox AJ, Lie RT, Moster D. Familial risk of cerebral palsy: population based cohort study. BMJ.

2014 Jul 15;349:g4294.

Wilcox AJ, Skjærven R, Lie RT. Familial patterns of preterm delivery: maternal and fetal contributions. Am J Epidemiol. 2008 Feb 15;167(4):474-9.