A two-stage approach to genetic risk assessment in primary care

Abstract

Genetic risk prediction models such as BRCAPRO are used routinely in genetic counseling for identification of potential BRCA1 and BRCA2 mutation carriers. They require extensive information on the counselee and her family history, and thus are not practical for primary care. To address this gap, we develop and test a two-stage approach to genetic risk assessment by balancing the tradeoff between the amount of information used and accuracy achieved. The first stage is intended for primary care wherein limited information is collected and analyzed using a simplified version of BRCAPRO. If the assessed risk is sufficiently high, more extensive information is collected and the full BRCAPRO is used (stage two: intended for genetic counseling). We consider three first-stage tools: BRCAPROLYTE, BRCAPROLYTE-Plus, and BRCAPROLYTE-Simple. We evaluate the two-stage approach on independent clinical data on probands with family history of breast and ovarian cancers, and BRCA genetic test results. These include population-based data on 1344 probands from Newton-Wellesley Hospital and mostly high-risk family data on 2713 probands from Cancer Genetics Network and MD Anderson Cancer Center. We use discrimination and calibration measures, appropriately modified to evaluate the overall performance of a two-stage approach. We find that the proposed two-stage approach has very limited loss of discrimination and comparable calibration as BRCAPRO. It identifies a similar number of carriers without requiring a full family history evaluation on all probands. We conclude that the two-stage approach allows for practical large-scale genetic risk assessment in primary care.

Keywords: BRCA1; BRCA2; BRCAPRO; BayesMendel; CancerGene.

Figure 1

Numbers of referrals made at each stage using a two-stage approach, as compared to using BRCAPRO only on all probands for (a) CGN+MDA and (b) NWH data. We denote by c₁ and c₂ the cutoffs used at the first and second stages, respectively. The number of probands whose carrier probability at the first stage exceed c₁ is denoted by n₁, and out of n₁, the number of probands with second stage carrier probability exceeding c₂ is denoted by n₂. When we evaluate BRCAPRO alone, the cutoff is labeled as c and the number of probands with carrier probability exceeding c is n₂. These numbers are further stratified by the carrier status in parentheses.

Figure 2

Sensitivity (Se.O) and Specificity (Sp.O) of the two-stage approach and BRCAPRO for (a) CGN+MDA and (b) NWH data. The x-axis has two sets of cutoffs, c₁ (first stage) followed by c₂ (second stage) below it. For BRCAPRO, only one cutoff (indicated by the second level c₂ values) is applicable.

Figure 3

Predictive Value Positive (PVP.O) and Negative (PVN.O) of the two-stage approach and BRCAPRO for (a) CGN+MDA and (b) NWH data. The x-axis has two sets of cutoffs, c1 (first stage) followed by c₂ (second stage) below it. For BRCAPRO, only one cutoff (c₂) is applicable.

Figure 4

Ratio of observed number of carriers to the expected number of carriers as predicted by the two-stage approach and BRCAPRO for (a) CGN+MDA and (b) NWH data.