The$Eﬀects$of$Environmental$Factors ... - Harvard University · Talk$Outline$ Background$info$&$study$design$ Analysis$methods$ Results,$conclusions,$moving$forward$

The Effects of Environmental Factors and the BRCA Gene:c Muta:on on Ovarian Cancer Risk

Andrea Lane Jennifer Osei

Nathalie Quiroz

Dr. Eric Tchetgen Tchetgen Ms. Kathy Evans

July 23, 2015

Talk Outline

●  Background info & study design

●  Analysis methods

●  Results, conclusions, moving forward

Part 1: Background

Ovarian Cancer

●  Ovarian cancer is a cancer that originates in the :ssue of the ovaries, female reproduc:ve gland that produces eggs.

●  “The American Cancer Society es:mates that in 2015, about 21,290 cases of ovarian cancer will be diagnosed and 14,180 women will die of ovarian cancer in the United States”

●  “The overall five-‐year survival rate for women with ovarian cancer is 45%”

Known Risk Factors

●  Gene:cs o  Breast Cancer Gene:c muta:ons (BRCA1 and BRCA2) o  Lynch Syndrome

●  Reproduc:ve History and Infer:lity o  Oral Contracep:ve Use o  Parity

●  Family History o  Ovarian Cancer o  Other female reproduc:ve cancers

●  Increasing Age ●  Hormone Replacement Therapy ●  Obesity

Known Risk Factors





Known Risk Factors





Known Risk Factors





Research Ques:on

Are there any significant interac:ons between the BRCA muta:on and the environmental factors: parity and oral contracep:ve use?

Research Study

●  Popula:on o Women in Israel (Ashkenazi Jews) o  1994-‐1999

●  Case-‐control Design o  Ovarian cancer is rare

●  Covariates

o  Parity, Oral Contracep:ve use, BRCA muta:on, Age, Ethnicity, Family History, Gynecology History, Cancer History

Descrip:ve Sta:s:cs

Descrip:ve Sta:s:cs

Part 2: Analysis

Logis:c Regression Models

1. Isola:ng variables of interest and examining interac:on terms logit(P(Y =1)) = β0 +β1G +β2E1 +β3E2 +β4GE1 +β5GE2

α = 0.05


2. Model with all variables logit(P(Y =1)) = β0 +β1G +β2E1 +β3E2 +β4C +...+β8C

3. Model with all variables and interac:on terms


logit(P(Y =1)) = β0 +β1G +β2E1 +β3E2 +β4GE1 +β5GE2 +...+β10C

Problem with Interac:on

1.  Sample size issue (Controls with BRCA)

2.  Not the best es:mate of interac:on coefficient

eβ3 = OR(G,E |Y =1)OR(G,E |Y = 0)

logit(P(Y =1)) = β0 +β1G +β2E +β3GE

Case – Only Assump:ons

1. Ovarian cancer is a rare disease

2. The BRCA gene:c muta:on and environmental factors are independent

OR(G,E |Y = 0) ≈OR(G,E)

1),( =EGOR

1)0|,( ==YEGOR⇒

Case -‐ Only Model

Now we need to es:mate: OR(G,E |Y =1)

logit(P(G =1)) = β0 +β1E

In the case-‐only model = in the general model β3β1

Part 3: Results

Research Ques:on -‐ Revisit

Are there any significant interac:ons between the BRCA muta:on and the environmental factors: parity and oral contracep:ve use?

Results : Interac:ons

•  Interac:on 1: BRCA and Oral Contracep:ve Use •  Interac:on 2: BRCA and Parity

Results: With Covariates

Interac:ons Accoun:ng for Covariates (N = 832)

Conclusions

●  Overall, the interac:on between BRCA and the environmental variables were not significant at the 0.05 level

●  Es:mate for the interac:on between BRCA muta:on and use of oral contracep:ves is posi:ve, indica:ng increase in the risk of ovarian cancer

●  Es:mate for the interac:on between BRCA muta:on and parity is nega:ve, indica:ng decrease in the risk of ovarian cancer

●  Data suggests use of oral contracep:ves reduces risk of ovarian

cancer in the overall popula:on

●  BRCA muta:on is the biggest indicator for ovarian cancer risk

Limita:ons

●  Retrospec:ve studies o  Self-‐reported data

●  Case-‐control study o  Cannot es:mate risk or rate, only odds ra:o

●  Case-‐only analysis o  limited to analysis of interac:ve coefficient

●  Generalizability

Future Research

●  More generalizable study popula:on

●  Rela:ng environmental factors to other types of cancer

●  Beier understanding of biological mechanisms

References

1.  McGuire, V. (n.d.). Rela:on Of Contracep:ve And Reproduc:ve History To Ovarian Cancer Risk In Carriers And Noncarriers Of BRCA1 Gene Muta:ons. American Journal of Epidemiology, 613-‐618.

2.  Modan, B., Hartge, P., Hirsh-‐Yechezkel, G., Chetrit, A., Lubin, F., Beller, U., . . . Wacholder, S. (2001). Parity, Oral Contracep:ves, and the Risk of Ovarian Cancer among Carriers and Noncarriers of a BRCA1 or BRCA2 Muta:on. New England Journal of Medicine N Engl J Med, 235-‐240.

3.  Ovarian Cancer Na:onal Alliance. (n.d.). Retrieved July 5, 2015, from hip://www.ovariancancer.org/about/sta:s:cs/

Acknowledgements

•  Dr. Eric Tchetgen Tchetgen •  Ms. Kathy Evans •  Dr. Rebecca Betensky •  Ms. Tonia Smith •  Ms. Heather Mane •  Ms. Ellie Murray •  Mr. Joshua Barback •  Harvard Summer Program in Biosta:s:cs and

Computa:onal Biology

Documents

The$Eﬀects$of$Environmental$Factors ... - Harvard University · Talk$Outline$ Background$info$&$study$design$ Analysis$methods$ Results,$conclusions,$moving$forward$