|                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |   |
|--------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------|
|                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |        |
| - Home
- About Us
- Meetings
- Reports
- Transcripts
- Background Materials
- Former Bioethics Commissions

  | *This staff paper was discussed at the March 2008 meeting. It does not represent the official views of the Council or of the U.S. government.*
The Future of Newborn Screening: Clouds on the Horizon? Staff Discussion PaperBy Adam Schulman, Ph.D. 
**Abstract.***This working paper is intended to aid discussion of the following ethical dilemma: For 40 years there has been a consensus that infants should be screened at birth only for conditions for which an effective treatment already exists. As we enter the age of genomic medicine, is this rule an outmoded dogma that ought to be overturned or a sound principle that ought to be preserved?*

Newborn genetic screening presents us with ethical quandaries that do not arise when adults undergo genetic testing. While adults can decide for themselves whether to be tested or not, newborn screening targets persons who have no say in the matter and who thus cannot give or withhold their consent. Though such screening may prove beneficial to children, it may also change their lives forever in ways they have no control over. Expanded newborn screening receives support from the principles of genomic medicine, which sanction the gathering of patients’ genetic data ever more systematically as well as ever earlier in life. Genomic medicine’s “need to know,” driven by the lofty ideal of providing care that is at once predictive, preventive, and personalized, inevitably comes into conflict with the individual’s right “not to know.” More gravely, the relentless logic of genomic medicine that fuels the expansion of newborn screening shows signs of driving genetic screening even further back in the life cycle, toward prenatal screening, i.e., toward prevention not of the child’s illness but of the child himself. As we enter the exciting age of genomic medicine, considerable forethought will be required to reap the benefits of genetic self-knowledge while avoiding its perils. The expansion of newborn screening must be carried out in full awareness of its impact, for good or ill, on the lives of our children, and care must be taken lest genomics merge heedlessly into eugenics and personalized medicine come to encompass the elimination of defective persons. 

 This paper will have five sections, addressing the following topics: first, where newborn screening is heading as we enter the age of genomic medicine; second, the debate over expanded newborn screening today; third, the debate over the future of newborn screening under genomic medicine; fourth, the case for vastly expanded newborn screening; and lastly, the case for caution.
I. Newborn Screening at the Dawn of the Genomic Era
The completion of the Human Genome Project in 2003 signaled the beginning of the age of genomic medicine. With the full mapping of the human genome, researchers are increasingly able to pinpoint errors in genes that cause or contribute to a multitude of conditions, from rare genetic disorders to common illnesses. On the basis of comprehensive genomic knowledge, physicians of the future will be able to tailor diagnosis and treatment to the unique genetic profile of the individual patient, thereby eliminating much of the guesswork of traditional “one size fits all” medical practice.

 To achieve its full potential, personalized medicine will require physicians to gather vast amounts of genetic information from their patients. The National Human Genome Research Institute (NHGRI) has announced the goal of reducing the cost of sequencing an individual human genome (currently about $10 million) first to $100,000 and then to $1,000. At that price point, thought to be reachable by 2014, an individual’s full genome could be added to his medical file as part of routine medical care—to supplement and in many ways to supersede the patient’s family medical history.

 In the meantime it is already feasible, using “gene chips,” microbeads, and other state-of-the-art multiplex technologies, to test an individual’s DNA for the presence of hundreds of thousands of distinct SNPs (single nucleotide polymorphisms), minute variations in the DNA sequence that can affect how the individual develops diseases and responds to pathogens, drugs, vaccines, and so forth. Already, a handful of private companies are offering, for as little as $1,000, to check your genome at over half a million points for known variations believed to correlate with particular traits, conditions, and susceptibilities.**1** Clearly, the genomic era is already upon us.

 Rapid medical and technological progress aided by the Human Genome Project is challenging both the practice and the principles of newborn screening. In 2002, the American College of Medical Genetics (ACMG) was commissioned by the federal government’s Maternal and Child Health Bureau to recommend a uniform panel of conditions to screen infants for at birth. Guided by the ACMG’s 2005 report, which recommended a panel of 29 core conditions and 25 secondary conditions,**2** most babies born today in the United States are screened at birth for between 30 and 50 genetic disorders, primarily by using tandem mass spectrometry (MS/MS) to detect abnormal levels of metabolites in the infant’s blood. At the same time, the National Institute of Child Health and Human Development (NICHD) is spearheading efforts to move beyond such limited, phenotypic methods of newborn screening toward DNA-based platforms that can “offer enormous opportunities to identify staggering numbers of potentially pathogenic mutations in a very large number of disease-associated genes.”**3**Many competent observers expect that, in the not too distant future, simple and inexpensive DNA-based multiplex platforms will be the standard instruments of newborn screening in most states (supplemented with phenotypic testing for conditions that require it).**4**

 Faced with the prospect of virtually unlimited expansion in the number of conditions (or at any rate the number of genetic markers) that can be simultaneously screened for, the question arises, what principles should dictate the inclusion or exclusion of a detectable genetic abnormality in the panel of conditions routinely screened for at birth? In particular, is it permissible to screen newborns for disorders for which there is as yet no effective treatment? The controversy on this issue may be said to have two phases: first, the current practical debate over limited expansion of the uniform screening panel, and, second, the more speculative debate over the future of newborn screening in the age of genomic medicine.
II. The Debate over Expanded Newborn Screening Today
Since screening for the metabolic disorder phenylketonuria (PKU) began in the 1960s, the ethical principles governing newborn screening have enjoyed a remarkably durable consensus. In an influential 1968 World Health Organization monograph, James Wilson and Gunnar Jungner developed ten “principles of early disease detection.”**5** According to their second principle, a disease should not be screened for unless there is an accepted treatment for patients found to have it. Of this principle Wilson and Jungner wrote: “Of all the criteria that a screening test should fulfill, the ability to treat the condition adequately, when discovered, is perhaps the most important.”**6** In 1994, an Institute of Medicine (IOM) report on Assessing Genetic Risks recommended that newborn screening “take place only when (1) there is a clear indication of benefit to the newborn, (2) a system is in place to confirm the diagnosis, and (3) treatment and follow-up are available for affected newborns.”**7** In 1995, the American Society of Human Genetics (ASHG) and the American College of Medical Genetics (ACMG) issued a joint report affirming that “timely medical benefit to the child should be the primary justification for genetic testing in children and adolescents,”**8** and this judgment was reaffirmed by a 1997 report issued by the NIH Task Force on Genetic Testing.**9** In 2000, a report by the American Academy of Pediatrics stated that a condition is a good candidate for newborn screening only if “the treatment for the condition is effective when initiated early, accepted among health care professionals, and available to all screened newborns.”**10** Finally, the ACMG’s 2005 report, while recommending a significant expansion in the number of conditions targeted by newborn screening programs, nonetheless affirmed that, for a condition to merit inclusion in a uniform newborn screening panel, there must be “demonstrated benefits of early detection, timely intervention and efficacious treatment of the condition being tested.”**11**

 Despite this apparently enduring consensus, the principle “Screen only if you can intervene” has not gone unchallenged. A 1975 report by a committee of the National Research Council (NRC, the working arm of the National Academy of Sciences) began by stating that newborn screening is appropriate when there is evidence that it provides “substantial public benefit,” i.e., benefit not limited to the timely and effective treatment of the infant’s condition.**12** The report went on to describe three forms of such benefit other than direct treatment: (1) to the infant (to provide management and support even when direct treatment is unavailable),**13** (2) to the family (to inform subsequent reproductive decisions),**14** and (3) to society (to provide knowledge of the true range and incidence of the condition).**15** The NRC report entertained the notion that, under some circumstances, “screening should begin before any treatment is available.”**16**

 Donald Bailey and colleagues have recently argued for an expanded conception of presumptive benefit that would justify newborn screening even in the absence of medical benefit to the child. In their view, newborn screening for disorders that currently have no cure or medical treatment nevertheless has the following merits: “(1) it allows for earlier psychosocial or therapeutic intervention; (2) it provides access to services that most parents would consider helpful for their children; (3) it provides access to support services that can have positive benefits for families; (4) it is consistent with literature on consumer preferences for information; and (5) it provides other social benefits that, in the absence of data indicating harm, justify their inclusion in newborn screening.”**17**

 A similarly expansive notion of public benefit, not limited to direct treatment of the child, can be found in the criteria by which the ACMG, in its 2005 report, recommended a uniform, expanded panel of conditions eligible for newborn screening. In assessing each testable condition for inclusion in the uniform panel, the authors of the ACMG report gave “overriding consideration” to benefits of early intervention for the individual screened (chiefly when there is a known and effective treatment), but they also gave weight to “benefits of early intervention for family and society,” including provision of genetic information to aid carrier detection, testing of other family members, and family planning (including prenatal diagnosis in subsequent conceptions).**18**

 A number of thoughtful commentators have raised questions about the wisdom of expanding the number of illnesses routinely screened for at birth, especially when the immediate benefits to the affected child are unclear. Some of the concerns raised include the lack of evidence-based efficacy studies, the problem of informed consent, the potential for psychosocial harm, worries about stigmatization and discrimination against the genetically unfortunate, and the challenges of providing genetic information, support, and counseling to affected families.**19**

 In a commentary on the ACMG’s 2005 recommendations on newborn screening, Jeffrey Botkin and colleagues urge a more cautious approach to expansion.**20** They point out that, even in its most celebrated and paradigmatic successes (such as PKU), newborn screening has proved to be a mixed blessing, with adverse consequences as well as benefits. They warn that each genetic illness is unique; that population-wide screening of asymptomatic individuals for uncommon diseases has rarely proved effective; that the benefits and risks must be carefully weighed on a condition-by-condition basis; and that rapid expansion of the uniform screening panel without adequate empirical studies would be unwise. 

 Norman Fost, one of Botkin’s co-authors, has written eloquently on the dangers of an overly enthusiastic embrace of expanded screening. In 1992 Fost examined unintended consequences of the screening programs for PKU and sickle cell anemia, among other illnesses, and drew an important general lesson: that screening asymptomatic individuals for genetic abnormalities is not a neutral gathering of information with no effect on the lives of those screened; instead, every screening program must be considered an experiment until benefits and risks have been clarified by well-designed empirical studies.**21** In remarks to this Council in 2005, Fost lamented that, despite “virtual unanimity on the principles of responsible genetic screening, and newborn screening in particular,”

…the guidelines are systematically ignored. That is, newborn screening has expanded like topsy, with the same mistakes that beleaguered the PKU program happening over and over again. That is, numerous screening and treatment programs have been implemented without testing, evaluation of the tests, without any systematic study of the sensitivity, specificity, or predictive value of the test, or of the interventions.**22**

Fost anticipated that states would rush to embrace expanded routine newborn screening, “testing without consent, without prior research, for dozens of conditions using tandem mass spectrometry.” And he foresaw, once multi-array DNA testing became cost-effective, an enormous expansion of newborn genetic screening without pausing for a careful illness-by-illness evaluation of the risks and benefits of routine screening. Fost warned of “a calamity involving every child in America, …the amount of harm, psychosocial harm that will occur to families and children, not to mention medical harm, is, in my view, going to be quite extensive.”**23**

 Responding to the ACMG’s expanded panel of 54 illnesses—and to the prospect of further expansions as new test modalities become available—Botkin and colleagues strongly urged the merits of implementing newborn screening within a *research paradigm*, involving thorough empirical studies to determine for each disorder whether it is suitable for routine screening. The questions that would need to be studied include: Do the benefits of screening for this disorder outweigh the harms, if any? What are the actual medical, psychological, and social outcomes for infants testing positive for the disorder? How common are false-positive results, and what are their consequences? What are the secondary benefits of screening to the family and to the public, and are they substantial enough to justify screening when the traditional standard of direct medical benefit to the child cannot be met? 

 Defending the ACMG’s recommendations, Rodney Howell (one of the project’s leaders) acknowledged that an expansion of screening will require a complex infrastructure (to support testing, counseling, treatment, and follow-up) that is not yet in place. But he defended the efficacy of newborn screening in general and pointed out that “there is little advantage at this time to discuss whether there should be expansion of newborn screening; it is occurring briskly at this very moment.”**24** Indeed, it is notable that both those urging caution and those enthusiastically embracing the expansion of newborn screening are more or less in agreement that rapid expansion is already taking place, and accelerated expansion in the future is all but inevitable.

Thus the current debate over newborn screening revolves around such practical questions as: Which particular conditions ought to be added to the uniform panel, and when? Should infants be screened for a condition only when effective treatment is available? Should secondary benefits to the family and to society be given some weight? How thoroughly should the specific benefits and risks be investigated before adding a condition to the panel? How cautious should we be about adding conditions to the panel when the benefits of screening are uncertain?

 For a number of reasons, however, the fine points of this debate over particular disorders and when to add them to the panel seem destined to be swept away by larger developments as we enter the genomic age. The future scope of newborn screening is likely to emerge on a greatly altered landscape, as is vividly suggested by Duane Alexander and Peter van Dyck in their recent article, “A Vision of the Future of Newborn Screening,” to which we now turn.
III. The Debate over Expanded Newborn Screening in the Genomic Era
In 2006, Duane Alexander, Director of the NICHD for more than two decades and thus one of the nation’s leading voices in pediatric medicine, coauthored an article with his colleague Peter van Dyck, openly calling the principle that “it is appropriate to screen only for conditions for which effective treatment already exists” a *dogma* that needs to be changed, by “broadening the concept of benefit from screening for the child to include the family.”**25** So far, at least, their point seems well within the mainstream of current debate over how liberally “benefit” should be understood. Yet Alexander and van Dyck go on to argue that the alleged dogma “dooms us to continued ignorance and unavailability of treatment because affected individuals are not identified until they exhibit symptoms, too late for effective preventive interventions to be tested or applied.” In their view, screening for conditions for which there is no effective treatment is justified because it can (1) reduce the time between onset of symptoms and diagnosis, thus avoiding the “diagnostic odyssey” to which many victims of rare genetic disorders are subject; (2) enable parents to make informed reproductive decisions; (3) permit adjunctive therapy and early intervention even when the child’s condition is incurable; and (4) enable the child to enroll in a registry of persons affected by the disorder, to be contacted if and when new experimental interventions are being tested. 

 In the course of their essay it becomes clear that Alexander and van Dyck are not merely calling for “an expanded notion of benefit” to be considered when evaluating individual disorders for inclusion in the panel. Instead, in their vision of the future of newborn screening, DNA-based multiplex platforms will be used to screen for “virtually all target conditions with one test system.”**26** More fundamentally, in their view every medically significant genetic marker should be assumed to be screenable *except those specifically excluded on a case-by-case basis.***27** The old dogma, “Screen only if you can intervene,” is to be replaced by a new principle, “Screen unless there is a compelling reason not to.” In other words, in the future as envisaged by Alexander and van Dyck, shortly after the birth of a child, the parents and pediatrician would be provided with a comprehensive survey of the baby’s genetic abnormalities and their medical significance. In what follows we shall denote this vision of a vastly expanded screening program by the phrase *universal newborn screening*.

 In a published response to Alexander and van Dyck, the distinguished British epidemiologist Nicholas Wald challenged their assertion that “the old dogma cannot be allowed to stand in the way of developing effective treatments for these rare genetic disorders.”**28** Wald reaffirmed the traditional view that screening for a condition should begin only once an effective treatment has been found. Of the four reasons Alexander and van Dyck gave for permitting screening in the absence of effective treatment, Wald found only the fourth had merit, viz., “that early detection might provide the opportunity for research into preventive therapies.” Even so, Wald argued, “this is not what most people expect from screening. They expect a personal benefit, not to be a potential candidate for a research study.” Screening for research purposes should, according to Wald, be “restricted to areas in which there is a reasonable expectation that such research will be conducted instead of recommending screening generally.”**29** Wald concluded that the “old dogma” in fact remains “a sound principle”: “There would need to be special and compelling reasons to screen for a disorder for which no effective remedy was available.”**30**

 In reply, Alexander and van Dyck wrote that Wald’s arguments, “on which policies have been based for nearly 50 years,” were precisely those that should be challenged.**31** In their view, Wald’s resistance to expanded screening indicates a failure to recognize the knowledge gained from a half-century of newborn screening and “the desires of parents for help with conditions other than the very few for which such effective treatment is available.” As they put it, “Our experience has shown an almost unanimous preference of parents for knowing the diagnosis in the newborn period rather than months or years later when symptoms developed.”**32** We shall revisit the question of parental preferences below.

 If Norman Fost’s prognostications are correct, this debate over vastly expanded newborn screening is likely to be won by the proponents. Assuming that in a matter of years or at most decades the Human Genome Project will bear fruit in the form of affordable whole-genome sequencing or at least affordable multiplex SNP genotyping, the vision of Alexander and van Dyck seems a plausible picture of a not-too-distant future in which infants are routinely screened at birth for almost all medically significant genetic markers (with a few conditions deliberately excluded), to be treated immediately when possible, and otherwise to be enrolled in registries to await trials of experimental therapies. Personalized genomic medicine will then start from the moment of birth, as the pediatrician will be in possession of a complete map of his young patient’s known genetic defects, vulnerabilities, and susceptibilities.

 What misgivings, if any, could cloud this bright prospect? The remainder of this working paper will try to shed some light on that question, first by explaining why the appeal of universal newborn screening is so powerful, and then by offering some grounds for caution and circumspection.
IV. The Case for (Vastly) Expanded Newborn Screening
Given that the current debate is mostly about whether to add this or that disorder to the limited panel of conditions for which newborns are routinely screened, why should we believe that in the future the default practice will be to screen all newborns for every known genetic abnormality? 

*The short answer is: because the logic of personalized medicine inexorably demands it.* Francis Collins, who has led the Human Genome Project since 1993, described in 2001 what genomic medicine would look like in its earliest stage:

By the year 2010, it is expected that predictive genetic tests will be available for as many as a dozen common conditions, allowing individuals who wish to know this information to learn their individual susceptibilities and to take steps to reduce those risks for which interventions are or will be available. Such interventions could take the form of medical surveillance, lifestyle modifications, diet, or drug therapy. Identification of persons at highest risk for colon cancer, for example, could lead to targeted efforts to provide colonoscopic screening to those individuals, with the likelihood of preventing many premature deaths.**33**

Taking up Collins’s example: colonoscopy is normally recommended to begin at age 50, but with a family history of colon cancer it is recommended to begin at 40 years or earlier. But as geneticists discover correlations between particular combinations of SNPs and elevated risk of colon cancer, it will increasingly be possible to adjust the time at which colonoscopy should commence to the specific genome of the patient, thereby catching many cancers at an earlier, treatable stage. In principle, the same sort of adjustment of routine screening schedules will be possible in the cases of other cancers, tremendously improving the odds of detecting and eliminating those cancers before they turn deadly. 

 Once personalized genomic medicine becomes standard medical practice for adults, the logic of providing physicians with this powerful tool earlier and earlier in the patient’s life will be inescapable. Even if cancers, for example, are relatively rare in children and adolescents, why wait until adulthood to uncover susceptibilities and vulnerabilities that could well be countered by changes in diet and life habits (to say nothing of prophylactic therapies) at an early age? As Collins suggests, “with increasing genetic information about common illnesses, this kind of risk assessment will become more generally available, and many primary care clinicians will become practitioners of genomic medicine….”**34** Since so many of our habits are formed in childhood, there will be compelling reasons for pediatricians to become genomic practitioners as well. To fulfill its promise of predictive and preventive as well as personalized care, genomic medicine will push the point of data collection to the moment of birth—if not earlier.

 Pressure to begin collecting genetic data earlier and earlier will also come with the establishment of biobanks, i.e., huge repositories of information that interlink human genotypes with lifelong medical histories. An example is the UK Biobank, whose database will cover 500,000 volunteers and will interlink their health, lifestyle, and environmental histories with gene maps of DNA extracted from their blood.**35** It will be crucial not only to collect genotypic data from a large number of patients, but to correlate that data with exact medical histories recorded over many years.**36** Most genetic determinants of disease are likely to be complex and polygenic, and the more these cross-linked databases are mined for significant correlations, the more we will learn about each patient’s differential risks and susceptibilities. Here too, the logic of personalized medicine dictates that the collection of genotypic data and its correlation with individual medical, environmental, and lifestyle histories should cover the whole human lifespan, not excluding adolescence, childhood, birth, and even gestation in the womb. Moreover, the birth of a child is arguably the most convenient moment at which to enroll him, with the cooperation of his parents, in the comprehensive data-gathering system on which his personalized medical care will be predicated. In fact, pediatric biobanks are already being established in this country, and it stands to reason that the most powerful and useful form of such databases would include comprehensive genotypic data and medical histories collected from infants starting at birth or even *in utero*.**37**

 The hope of finding a cure for rare and as yet untreatable genetic disorders will provide a powerful incentive for comprehensive newborn screening. Disorders that afflict only a handful of persons each year are more difficult to study than more common diseases whose victims are easy to locate and study. An obscure disorder for which there is as yet no treatment is more likely to be elucidated and ameliorated or cured if newborn screening gives the medical community an accurate picture of the prevalence of the disease as well as early access to as many of its sufferers as possible. Genomic medicine offers a compellingly systematic approach to the search for treatment of such illnesses, including the following methodical steps: universal genetic screening at birth, followed by enrollment of all afflicted patients in a biobank of genotypic data; careful study of the course of the illness in each patient, with all significant medical histories entered in the biobank; and finally, when innovative therapies become available, easy access to pools of potential research subjects, to be contacted and enrolled in experimental trials. Surely it will be seen to be in the patient’s interest, broadly understood, to push his incurable genetic ailment into the column of treatable illnesses, even if no actual treatment is available at the time of his diagnosis. 

 With comprehensive screening, there is hope that the psychosocial consequences of testing positive for a genetic ailment will be less severe. When knowledge of genetic abnormalities is rare, the news that one carries a dangerous and defective gene is potentially devastating. It can entail debilitating anxiety, depression, and despair, not to mention stigmatization and discrimination by others. This is one of the strongest reasons for protecting the individual’s right of informed consent with respect to genetic testing, a right that is admittedly compromised when parents (or state governments) make the decision to have children genetically screened. But a case can be made that, with the full flourishing of genomic medicine and the routine gathering of thousands of data points from every human genome, the stigma attached to most genetic defects will largely dissipate, and along with it some of the most severe psychological sequelae. It will be better understood then that every one of us, without exception, carries a multitude of minute genetic variations, some of them favorable to health and happiness, others less auspicious. The sense that we are all in the genetic lottery together, and no one is simply a winner or a loser, may well provide the best foundation for a healthy and realistic attitude toward the vicissitudes of inheritance. This is not to say that the discovery that one carries a fatal or incapacitating gene defect, like the trinucleotide repeats that cause Huntington’s, will be easy to bear; but it does suggest that a comprehensive transformation of American medicine in the genomic direction will render genetic disease as a whole less horrifying and isolating.

 Finally, one can anticipate growing pressure from parents and advocacy groups to embrace rapid expansion of newborn screening.**38** Alexander and van Dyck noted, in their response to Wald, the “almost unanimous preference of parents for knowing the diagnosis in the newborn period.”**39** And indeed, studies have consistently shown strong (and growing) public support for genetic screening, especially among parents of children with genetic conditions.**40** Parents in the latter group seem to believe that they have a *right to know* whether their child has a genetic disorder, even if its untreatable; and they believe that such knowledge is good.**41** Notwithstanding the traditional principle that we should screen only for conditions that can be effectively treated, American parents seem increasingly willing if not eager to learn whatever they can about their children’s health, including any genetic abnormalities they might be born with.**42** Such parents may be exhibiting a tendency that Alexis de Tocqueville noticed in Americans as long ago as 1831: he found that Americans follow a Cartesian “philosophical method” even without ever having read the writings of Descartes. According to Tocqueville, it is characteristic of Americans to take tradition merely as information, to treat facts as a useful study for making things different and better, to seek the reason for things by themselves, and to strive for results without allowing themselves to be bound to any particular means.**43** In short, if their child has a problem, American parents simply want to know everything they can about it. That tendency may help to explain why the American public today, when surveyed, often shows more enthusiasm for expanded newborn screening than pediatricians do.**44**Whether it is indeed the parents’ *right* to decide on behalf of their young child that every genetic abnormality should be brought to light, is another question.

 It would be difficult to exaggerate the role of patient advocacy groups in pressing for the expansion of newborn screening.**45** As Jennifer Howse and colleagues put it, “Expansion of NBS has been driven primarily by a combination of advances in technology and medical treatment, and the sustained advocacy efforts of consumers and voluntary health organizations.”**46** Donald Bailey and colleagues noted that, during public commentary on the ACMG’s 2005 report, every advocacy group that commented endorsed the uniform screening panel and noted a range of benefits that would result from expanded screening. Moreover, “there was no mention of any risks or burdens of screening other than to discount arguments that conditions for which there is no proven medical treatment for the child should not be included in newborn screening.”**47** Parents who discover that their newborn child suffers from a rare genetic illness are quite likely to add their support to groups calling both for universal screening and for increased funding of research to find a cure. Undoubtedly, such vigorous advocacy of uniform screening makes a good deal of sense under the paradigm of genomic medicine. But it also means that those promoting the agenda of personalized genomic medicine and universal screening have a strong and energetic natural ally in the parents of genetically afflicted children and the groups that represent them.
V. The Case for Caution
We have seen that there are powerful arguments—and powerful technological and social forces—favoring the eventual realization of Alexander and van Dyck’s vision: universal DNA-based screening of newborns, with all genetic markers of medical interest included by default, and perhaps only a handful of disorders excluded on a case-by-case basis. It may in fact be impossible to hinder the relentless logic of genomic medicine from assimilating the practice of newborn screening to its all-embracing paradigm. Nonetheless, even if these future developments are virtually unstoppable, it would be prudent to remind ourselves of some of the reasons for doubting whether the new practice will be altogether benign. We at can at least approach the future with our eyes open, alert for signs of peril amidst the progress. 

 Many of the same concerns that have been expressed in regard to limited expansion of the newborn screening panel would*a fortiori*be applicable in the case of universal newborn screening. Norman Fost’s judgment that every genetic disorder is different, and that every screening is an experiment with potentially bad as well as good consequences, would be all the more pertinent in the event of a greatly expanded screening panel. At the very least, we would need to plan for a hugely expanded infrastructure for testing and confirming, sorting out false-positives, counseling families, and assessing the outcomes for the affected children. 

 One example will suffice to show how complex and elusive are the benefits and harms involved in each proposed screening protocol. The case of Duchenne muscular dystrophy (DMD) has been examined with great sensitivity by Lainie Friedman Ross, whose review of the case we draw on here.**48** DMD is an X-linked degenerative disease of the muscles that affects about 1 in 3,500 males. Symptoms usually begin before the age of 6 and lead to braces, wheelchair dependence, and death before the age of 30. There is considerable support for newborn screening of DMD even though it does not meet the Wilson-Jungner criteria of having an accepted treatment and an agreed policy on whom to treat. As Ross writes, “the main concern is whether early diagnosis improves prognosis.”**49** The standard treatment with corticosteroids has deleterious side effects and may be inappropriate for younger boys. That might suggest delaying screening to later in childhood; but some argue that “avoiding the diagnostic odyssey” is reason enough to screen at birth. But perhaps it would be better to improve pediatricians’ abilities to recognize early symptoms of DMD; for early diagnosis can lead to insurance discrimination because of a “pre-existing condition”; it can also cause unnecessary psychological harm. On the other hand, there are data indicating that early screening is the only effective way to diagnose DMD without considerable delay. Some argue for DMD screening as a way to assist “reproductive decision-making” and “life planning”; but these alleged benefits to the family must be weighed against the potential harms of diagnosing the child months or years before he becomes symptomatic, harms that include needless anxiety, disruption of the parent-child bond,**50**and the possibility that parents will misuse the information**51** or seek out dangerous alternative treatments, not to mention the ill effects of false-positives.

 Despite the unclear benefits of screening for DMD at birth, voluntary screening is offered in some countries, usually requiring explicit consent from the parents. In Wales, where informed consent is required, as many as 94% of parents agree to the screening at birth. It is not at all clear that this extraordinarily high participation rate reflects a careful weighing by the parents of the benefits and risks of screening for DMD. In Germany, where voluntary screening is offered between 1 and 12 months of age, only 5% of parents elect to participate; again, this low rate need not reflect a thoughtful rejection by the parents, since it is also hard to get parents to comply with immunizations during the first year. All in all, it is entirely unclear whether the participation rate should be 5%, 94%, or somewhere in between, and the record of DMD screening does not inspire confidence in parents’ capacity for informed consent when the harms and benefits are so doubtful and so evenly balanced. Multiply this example a hundred or a thousand fold and you begin to see the impenetrable difficulty of deciding whether a vastly expanded newborn screening panel does more good than harm.

 We presented above the argument that, with universal newborn screening, a sense that everyone has his own share of genetic imperfections and that “we are all in this together” might soften the impact of any bad news. The psychosocial burdens, to children as well as to parents, of living with an identified genetic abnormality, would certainly be more widely felt if every couple were to go home from the hospital with a virtual avalanche of information about the genetic defects and susceptibilities of their newborn child. But we would then be in uncharted territory, and it is not at all clear how human beings would adapt to such a massive increase in genetic self-knowledge. More precisely, we are speaking here of a massive increase of self-*information*, which does not automatically translate into wisdom or genuine self-knowledge. 

 As for the information itself, to whom will it properly belong? Does it belong to the child alone, to use or to disregard as he sees fit on reaching the age of majority? Or do parents (as some of them seem to believe) have an unlimited right to know the genetic abnormalities of their children? Do physicians have a claim on such information once it exists? Should the state, in the interest of building ever more useful genomic databases, have a presumptive right to “biobank” the child’s genotypic data? If newborn screening detected a range of unfavorable predispositions in the child’s genome, would they amount to “pre-existing conditions” that insurers or even potential employers would be entitled to consult before offering the patient health insurance or employment?

 These questions point to the inevitable tension between newborn screening and the principle of informed consent. Ideally, we would want a momentous decision such as whether to be tested for a serious genetic disorder to be made by the patient himself, with full understanding of the implications of a positive result. With newborn screening we allow the parent (or the state, if the screening is mandatory) to make that decision in the infant’s behalf, but such a transfer of responsibility raises serious ethical questions. The case of Huntington’s disease is instructive here. As noted above, Huntington’s is a late-onset neurological disorder, always fatal and at present untreatable. It is a dominant and fully penetrant Mendelian disorder, which means that children of a parent who has been diagnosed with Huntington’s have a 50% chance of having the gene and the disease themselves. The defective gene has been identified, and there is a definitive DNA-based test for its presence. Nancy Wexler has written with passion and eloquence on the tremendous complexity of the question of whether someone at risk for Huntington’s should have himself tested.**52** In the end she concludes that there is no right decision for everyone, and that each person at risk must be allowed to make that decision for himself after reaching young adulthood. While Huntington’s is far from typical of most genetic disorders, Wexler draws some general conclusions: above all, that 

truly informed consent, including a full psychological appreciation of the ramifications of the information, must be the principle upon which testing programs are designed. Information should not be foisted on someone without permission.**53**

As there is currently no treatment and no medical benefit from early detection, and a positive diagnosis is so potentially devastating, there has been widespread agreement that Huntington’s is one of the genetic disorders least suitable for routine screening, especially at birth or in early childhood. Even Alexander and van Dyck mention it as a prime candidate for exclusion from a greatly expanded newborn screening panel. It is reasonable, in fact, to try to range genetic disorders on a continuum, with those like PKU that unquestionably merit newborn screening (and where the patient’s right of informed consent is properly waived) at one end, and those like Huntington’s that should be left up to the individual at the other end. Yet it is quite likely that the psychological complexity of the personal decision whether to be tested for Huntington’s would also be present in the case of other genetic disorders even if they are not fully penetrant and invariably fatal. Deciding to screen for a multitude of conditions means taking from the child the right to decide these questions for himself when he has reached an age of sufficient maturity and thoughtfulness. Although nominally exercised for the benefit of the child, routine newborn screening is inevitably in some measure a violation of the child’s right “not to know,” if that were his choice. This may be a price worth paying but it ought to be paid in full awareness of its meaning.

 Advocates of an expanded notion of “benefit” often extol the utility of newborn screening for helping parents make future reproductive decisions (e.g., adoption, egg or sperm donation, IVF and PGD, amniocentesis and abortion, etc.). But this notion of “benefit to the family” is not unproblematic. First, as Nicholas Wald has noted, if the putative benefit to the family is to be realized by preventing the birth of siblings with the detected genetic defect, then it would make more sense to screen for the defect prenatally, so that the family is not burdened with even one defective child. Putting it so callously suggests that screening for family planning purposes is morally questionable. If we test an infant, not in the hope of providing treatment for his condition, but with a view to making sure that no further children come into the family with the same defect, aren’t we in effect telling the child that he was in some ways a regrettable mistake—that, had we known his genetic makeup in advance, we would have tried to prevent his birth? To the affected child, family planning in this sense means not “limiting the incidence of a defective gene” but “preventing the birth of any more kids like me.” Here the laudable goal of reducing the incidence of genetic disease comes into collision with the wish and the obligation to treat every family member as a being with inherent and equal value. Moreover, should the uniform panel of conditions be greatly expanded, the propriety of its use for family planning purposes would become even more questionable. Suppose that expanded screening of an infant reveals not a fatal and incurable disease but instead a host of genetic variants, each of which merely confers elevated risk for some condition or other? Who is to say at what point an uncovered defect becomes serious enough to warrant preventing the birth of other children who might carry it? At what point have we crossed the line from legitimate family planning to capricious and morally dubious eugenics?

 Indeed, the expansion of newborn screening, however reasonable it may be in itself, seems symptomatic of a broader phenomenon, a sort of Faustian imperative driving the search for genetic knowledge back to earlier and earlier points along life’s path. Neither preimplantation genetic diagnosis (PGD) nor amniocentesis is new, but it seems likely that as time goes on these procedures will come to seem more and more like routine options for prospective parents. Should the information gleaned from these tests seem sufficiently “negative,” some parents will be tempted to discard the “defective” embryo or abort the “defective” fetus, and that choice will no doubt be justified as “good” for someone: for the unborn child, for the unimplanted embryo, for the parents themselves, for the future siblings, or for society at large. In this way, the blameless intention to diagnose and treat our children’s illnesses will have drifted into the rather more sinister project of purifying future generations of their undesirable members. The specter of “eugenicide” hovers over the eagerly anticipated marriage of newborn screening with genomic medicine. 

 There is also a danger that, under the regime of genomic medicine and universal genetic screening, there will be a blurring of the distinction between genuine disease and mere *difference*. Only a small proportion of the abnormal gene variants uncovered by universal screening will lead directly and inexorably to serious illness. Typically, medically important SNPs will merely correlate (often in combination with other SNPs) with elevated susceptibilities for various medical conditions, and even these correlations will be unpredictable and highly variable, depending on a host of uncontrollable factors. The important discipline of *epigenetics* teaches that an individual’s actual health will be a complex result of genetic and environmental factors and will not be determined simply by his genes. Yet members of the public, ignorant of these subtleties, may have an exaggerated idea of the degree to which “bad” genes doom us to dreadful outcomes. Thus, with expanded newborn screening, significant decisions may often be made by parents in light of the identification of a genetic “abnormality” in their child that might end up having no clinical expression at all. Accordingly, it remains an open question whether all this information about the child’s possible medical future will be used for his benefit and will not shape in adverse ways the parents’ view of their child, his value, and his prospects for happiness. Furthermore, what will it be like for the child to grow up in possession of this vast storehouse of genetic information about himself? Will he see it as an entirely beneficial resource, to be used throughout his life to improve his health, adjust his habits and lifestyle, and assist his physicians when diagnosis proves elusive? Or will it instead be a burden to him, weighing him down with a fatalistic sense of his limitations and lost possibilities? 

 Such reflections lead, finally, to the deeper and more troubling question of the value of knowledge itself for human happiness. As Nancy Wexler wrote: 

The blind seer Tiresias confronted Oedipus with the quintessential dilemma of modern genetics: “It is but sorrow to be wise when wisdom profits not.”**54**

The presumption of modern science, including medical genetics, has always been that knowledge is fundamentally good for man, and that the more we know about ourselves the better we will be able to live the kind of lives we want to live. Yet the truth of this supposition remains in doubt as we lift the lid of the Pandora’s box of our genomic inheritance. Surely there is much information there that, used wisely, will improve our lives and help free us from illness, infirmity, and uncertainty. Yet there is also the possibility that such knowledge will be misused or misinterpreted, that it will tempt us to stigmatize and discriminate against the genetically unfortunate, and that under its weight some of us will incline toward fatalism and despair. There is, finally, the disturbing prospect that, should universal newborn screening become habitual and routine, universal prenatal screening would come to seem attractive as well, as the logical next step toward the perfection of “predictive and preventive” genomic medicine. Why prevent the disease when it would be simpler to prevent the patient? In view of these serious concerns, it would seem fitting for this Council to try to foster a national conversation about the ethical challenges that await us if and when universal newborn screening becomes an accomplished fact. 

_______________________ 
FOOTNOTES
1. See, for example, the websites www.23andme.com and www.decodeme.com, each of which offers to test a client’s DNA for several hundred thousand known SNPs; in contrast, www.knome.com offers whole genome sequencing at a special introductory price of $350,000 for the first twenty clients. For a thoughtful discussion of some ethical and legal implications of the $1,000 genome, see John A. Robertson, “The $1000 Genome: Ethical and Legal Issues in Whole Genome Sequencing of Individuals,” American Journal of Bioethics 3 (2003): W35-W43.

2. American College of Medical Genetics, Newborn Screening: Toward a Uniform Screening Panel and System (Washington, D.C.: 2005). 

3.  Duane Alexander and James W. Hanson, “NICHD research initiative in newborn screening,” Mental Retardation and Developmental Disabilities Research Reviews 12 (2006): 301-304, p. 302.

4.  Nancy S. Green and Kenneth A. Pass, “Neonatal screening by DNA microarray: spots and chips,” Nature Reviews Genetics 6 (2005): 147-151.

5.  James M. G. Wilson and Gunnar Jungner, Principles and Practice of Screening for Disease (Geneva: World Health Organization, 1968), pp. 26-27. Wilson was Principal Medical Officer for the Ministry for Health in London, and Jungner was Chief of the Chemistry Department in Sahlgren’s Hospital, Goteborg, Sweden. The ten Wilson-Jungner principles are:

1. The condition sought should be an important health problem.                2. There should be an accepted treatment for patients with recognized disease.                3. Facilities for diagnosis and treatment should be available.                4. There should be a recognizable latent or early symptomatic state.                5. There should be a suitable test or examination.                6. The test or examination should be acceptable to the population.                7. The natural history of the condition, including development from latent to declared disease, should be adequately understood.                8. There should be an agreed policy on whom to treat as patients.                9. The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.              10. Case-finding should be a continuing process and not a “once and for all” project.

6.  Ibid., p. 27.

7.  Committee on Assessing Genetic Risks, Institute of Medicine, Assessing Genetic Risks: Implications for Health and Social Policy, Lori B. Andrews, Jane E. Fullarton, Neil A. Holtzman, and Arno G. Motulsky, eds. (Washington, D.C.: National Academies Press, 1994). Quoted from the report’s Executive Summary, p. 5.

8.  American Society of Human Genetics, American College of Medical Genetics, “Points to consider: Ethical, legal, and psychosocial implications of genetic testing in children and adolescents,” American Journal of Human Genetics 57 (1995): 1233-1241, p. 1233. 

9.  Neil A. Holtzman and Michael S. Watson, Promoting safe and effective genetic testing in the United States: Final report of the Task Force on Genetic Testing (Bethesda, MD: National Institutes of Health, 1997).

10.  American Academy of Pediatrics Newborn Screening Task Force, “Serving the family from birth to the medical home. Newborn screening: A blueprint for the future,” Pediatrics 106 Supplement (2000): 389-427, p. 394.

11.  American College of Medical Genetics, Newborn Screening: Toward a Uniform Screening Panel and System (Washington, D.C.: 2005). 

12.  National Research Council Committee for the Study of Inborn Errors of Metabolism, Genetic screening programs, principles, and research (Washington, D.C.: National Academy of Sciences, 1975), p. 1.

13.  Ibid., p. 15.

14.  Ibid., chapter IV, section 6, “Screening to Provide Reproductive Information,” pp. 116-140.

15.  Ibid., chapter IV, section 7, “Screening for Enumeration, Monitoring, and Surveillance,” pp. 141-149.

16.  Ibid., p. 90.

17.  Donald B. Bailey, Jr., Debra Skinner, and Steven F. Warren, “Newborn Screening for Developmental Disabilities: Reframing Presumptive Benefit,” American Journal of Public Health 95 (2005): 1889-1893, p. 1889.

18.  On expansive notions of benefit in the ACMG’s report, see also Donald B. Bailey, Jr., Laura M. Beskow, Arlene M. Davis, and Debra Skinner, “Changing Perspectives on the Benefits of Newborn Screening,” Mental Retardation and Developmental Disabilities Research Reviews 12 (2006): 270-279. Significantly, despite the liberal definition of benefit used in the ACMG’s report, some commentators still found fault with the report’s exclusion of conditions that lacked an “efficacious treatment.” Sharon Terry, President and CEO of Genetic Alliance—“an international coalition comprised of more than 600 advocacy, research, and healthcare organizations that represent over 14 million individuals with genetic conditions and their interests”—wrote the following during public commentary on the ACMG’s report: “[A]s the ACMG’s expert groups evaluated conditions for inclusion in the uniform panel, significant consideration was given to whether or not there was an ‘efficacious treatment’ available. While Genetic Alliance respects the logic behind this particular qualification, we believe that the traditional medical model that this type of criterion reflects may not be the most appropriate one for newborn screening. That is, while the medical community may not consider a particular treatment ‘efficacious,’ an affected family might find that same treatment essential. Our community of consumers—14 million people living with genetic conditions—knows that the medical definition of treatment is more narrow and limited than the one they experience.” (Sharon F. Terry, “Comments to Secretary’s Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children,” May 5, 2005, available online at www.geneticalliance.org/ws_display.asp?filter=policy.newborn.sachdgdnc.)

19.  See especially Jeffrey R. Botkin, “Research for Newborn Screening: Developing a National Framework,” Pediatrics 116 (2005): 862-871; Nicola J. Kerruish and Stephen P. Robertson, “Newborn screening: new developments, new dilemmas, Journal of Medical Ethics 31 (2005): 393–398; Holly A. Taylor and Benjamin S. Wilfond, “Ethical issues in newborn screening research: lessons from the Wisconsin cystic fibrosis trial,” Journal of Pediatrics145 (2004): 292-296; and Beth A. Tarini, “The current revolution in newborn screening: new technology, old controversies,” Archives of Pediatrics and Adolescent Medicine 161 (2007): 767-772.

20.  Jeffrey R. Botkin, et al., “Newborn Screening Technology: Proceed With Caution,” Pediatrics 117 (2006): 1793-1799.

21.  Norman Fost, “Ethical implications of screening asymptomatic individuals,” FASEB (Federation of American Societies for Experimental Biology) Journal 6 (1992): 2813-2817, p. 2814.

22.  Norman Fost, presentation before the President’s Council on Bioethics, December 8, 2005, available online at www.bioethics.gov/transcripts/dec05/session1.html. Sharing Fost’s pessimism, Jeffrey Botkin has asserted that, of the 29 core ACMG conditions, only PKU and perhaps five other conditions (including congenital hypothyroidism and the hemoglobinopathies such as sickle cell anemia) have treatments that are known to work. Of some of the more problematic tests (those for the rare amino acid metabolism disorders citrullinemia, arginosuccinic aciduria, and tyrosinia) Botkin has said, “The conditions are not well understood, the spectrum of the disease is not well understood, it is uncertain how efficacious the treatments are, and it is uncertain how well people can tolerate the treatment.” See Gina Kolata, “Panel to Advise Testing Babies for 29 Diseases,” The New York Times, February 21, 2005. Regarding the metabolic disorders included in the ACMG’s recommended panel, Marvin Natowicz has commented: “For some disorders we do not know what a ‘true’ positive screening test means at the time of diagnosis, and in some instances, an abnormal biochemical screening result will have no clinical correlate at all.” See Marvin Natowicz, “Newborn Screening—Setting Evidence-Based Policy for Protection,” New England Journal of Medicine, 353 (2005): 867-870, pp. 868-869.

Botkin and colleagues contrast the expansive optimism of the ACMG report with the cautious spirit of a 2004 study in the UK whose authors were “unable to find sufficient data to demonstrate cost-effectiveness of MS/MS technology for conditions other than PKU and medium chain acyl-CoA dehydrogenase deficiency within the UK system.” Jeffrey R. Botkin, et al., “Newborn Screening Technology: Proceed With Caution,” Pediatrics 117 (2006): 1793-1799, p. 1796. See also Neil A. Holtzman, “Expanding newborn screening: how good is the evidence?” JAMA 290 (2003): 2606–2608.

23.  Norman Fost, presentation before the President’s Council on Bioethics, December 8, 2005.

24.  R. Rodney Howell, “We Need Expanded Newborn Screening,” Pediatrics 117 (2006): 1800-1805, p. 1802.

25.  Duane Alexander and Peter C. van Dyck, “A Vision of the Future of Newborn Screening,” Pediatrics 117 Supplement (2006): S350-354, p. S352. In his presentation to the Council on June 23, 2006, Alexander traced the origin of the dogma to the recommendation, in the 1975 NRC report cited above, that (in his words) “you should not screen for anything that you don’t have an effective treatment for.”

26.  Ibid., pp. S351, S353. In his presentation before this Council on June 23, 2006, Dr. Alexander elaborated: “[Tandem mass spectrometry] still doesn’t go as far as we need it to go. And so we’re looking at potential DNA-based systems. If we could have this, we could screen for basically anything we have the gene for…. The numbers go into the hundreds. And each time we discover a new gene or a new abnormality of a gene the number of conditions would go up.

“…[T]hese are things that are coming along and that we are investing in, trying to develop an enhanced capability to screen, and to have a test that is so attractive, so simple, and not too expensive, so that every state will want to use this in their screening program, and no longer will there be this state-to-state variability, so that what you get screened for depends on the state in which you’re born.”

27.  In their article, Alexander and van Dyck mention only Huntington’s disease (an invariably fatal, as yet untreatable, adult-onset, Mendelian dominant, neurological disorder) as a possible candidate for exclusion. It is not clear what other disorders they would put in the same category. At Duane Alexander’s June 23, 2006, appearance before the Council, Council Member Floyd Bloom pointed out that Huntington’s would seem to fulfill “all of the criteria by which you listed the tests that you want to include, even though we can’t treat them.” (For an online transcript, see www.bioethics.gov/transcripts/june06/session5.html.) If a new treatment were developed that, when started early in life, produced even a modest decrease in the morbidity or mortality of Huntington’s disease, I imagine that Alexander and van Dyck would move Huntington’s firmly into the “screen” column. 

28.  Nicholas Wald, FRS, “Neonatal Screening: Old Dogma or Sound Principle?” (letter to the editor), Pediatrics 119 (2007): 406-407.

29.  Ibid., p. 406. Wald found the other three reasons offered by Alexander and van Dyck insufficient to justify a presumption in favor of screening: (1) The “diagnostic odyssey,” Wald suggests, is a reason not to introduce population-wide screening, but to educate physicians to be better diagnosticians; (2) the argument for newborn screening as a way to assist parents with reproductive decisions is really, says Wald, an argument for prenatal screening; (3) as for adjunctive therapies in the absence of curative therapies, Wald says a persuasive case would have to be made for each disorder.

30.  Ibid., p. 406.

31. Duane Alexander and Peter C. van Dyck, “Neonatal Screening: Old Dogma or Sound Principle?” (in reply), Pediatrics 119 (2007): 407.

32.  Ibid.

33.  Francis S. Collins, “Implications of the Human Genome Project for Medical Science,” JAMA 285 (2001): 540-544, pp. 543-544.

34.  Ibid., p. 544.

35.  See their website at www.ukbiobank.ac.uk.

36. The “Genomics and Personalized Medicine Act of 2007,” sponsored in the 110th Congress by Senator Barack Obama in order “to secure the promise of personalized medicine for all Americans by expanding and accelerating genomics research and initiatives to improve the accuracy of disease diagnosis, increase the safety of drugs, and identify novel treatments,” calls for the establishment of “a national biobanking distributed database for the collection and integration of genomic data, and associated environmental and clinical health information, which shall facilitate synthesis and pooled analysis of such data.” The text of the proposed legislation may be found online at http://www.govtrack.us/congress/billtext.xpd?bill=s110-976.

37.  See Jocelyn Kaiser, “U.S. Hospital Launches Large Biobank of Children’s DNA” (News of the Week: Genetics), Science 312 (2006) 1584-1585. According to Kaiser, Children’s Hospital of Philadelphia plans “to analyze DNA from 100,000 children and begin searching for links to childhood diseases such as asthma, diabetes, and obesity.” See also Alon B. Neidich, et al., “Empirical data about women’s attitudes towards a hypothetical pediatric biobank,” American Journal of Medical Genetics Part A 146A (2008): 297-304, and David Kaufman, et al., “Ethical Implications of Including Children in a Large Biobank for Genetic-Epidemiologic Research: A Qualitative Study of Public Opinion,” American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C (2008): 31–39.

38.  Some of the same social pressures are at work in driving the states to offer the maximal panel of conditions for newborn screening. As Jeffrey Botkin put it in remarks to the Council on February 3, 2006, “I think there’s a strong social attitude that screening is a good thing, and I see it in the paper every morning with the body scanners. You know, spend 600 bucks. Detect disease early and save your life. Well, there’s no data to support any of that, but it’s part of the social consciousness now, and I think how that’s translated into newborn screening is the strong sense that if you’ve got five tests, that's good. If you've got 20 tests, that’s really terrific, and any self-respecting state, you know, should not have less than 40 tests on its panel.” (Remarks available online at www.bioethics.gov/transcripts/feb06/session6.html.)

39.  Duane Alexander and Peter C. van Dyck, “Neonatal Screening: Old Dogma or Sound Principle?” (in reply), Pediatrics 119 (2007): 407.

40.  For example, Fragile X syndrome, the most common inherited form of mental retardation, does not meet the criteria for routine newborn screening, as there is currently no cure or medical treatment. But in a recent survey of parents of children with Fragile X, large majorities (over 90%) favored screening newborns both for the genetic disorder and for carrier status. See Debra Skinner, Karen L. Sparkman, and Donald B. Bailey, Jr., “Screening for fragile X syndrome: parent attitudes and perspectives,” Genetics in Medicine 5 (2003): 378–384. 

 Another example: Although professional guidelines recommend against testing minors for adult-onset genetic conditions, Angela Bradbury and colleagues found that, among parents who are carriers of the BRCA mutations (which correlate with increased risk for breast cancer) and their adult children, as many as 40% supported genetic testing of minors for the mutations. See Angela R. Bradbury, et al., “Should genetic testing for BRCA1/2 be permitted for minors? Opinions of BRCA mutation carriers and their adult offspring,” American Journal of Medical Genetics Part C: Seminars in Medical Genetics 148C (2008): 70-77.

41.  In a 1998 survey, North American parents (mostly mothers) of children with diagnosed or possible genetic conditions were asked, “Some conditions can be found at birth through a simple blood test. Sometimes there is no treatment for the child. In these cases, the main purposes of testing the newborn child are to find out if this child has a genetic condition and to let the parents know that they could have another child with the same condition. If you were a parent, would you want your newborn child tested right away so that you could find out if your next child would have a genetic condition?” 71% said “yes,” 11% said “no,” and 18% said “I don’t know.” See Dorothy C. Wertz and John C. Fletcher, Genetics and Ethics in Global Perspective (Dordrecht: Kluwer Academic Publishers, 2004), p. 72, and Dorothy C. Wertz, “Ethical issues in pediatric genetics: views of geneticists, parents and primary care physicians,” Health Law Journal 6 (1998): 3-42. The conductors of the survey report that, “in write-in comments, parents said they had a right to know, that the information would help them relate to their child, and that they wanted the information so they could decide about having another child.” (Wertz and Fletcher, loc. cit.)

42.  Surveying the general public on these questions, a 2007 report released by the University of Michigan C. S. Mott Children’s Hospital National Poll on Children’s Health found that 54% of adults endorsed genetic testing of children even if no effective treatment is available, and 38% of parents were willing to have their children’s DNA stored in a government DNA biobank. The poll found that the adult children viewed such testing even more favorably than their parents, suggesting that succeeding generations are growing more and more comfortable with idea of routine genetic screening. (Report available online at www.med.umich.edu/opm/newspage/2007/NPCH_4.pdf.)

43.  Alexis de Tocqueville, Democracy in America, vol. 2 (1840), part 1, chapter 1, “On the philosophic method of the Americans.” 

44.  Kruti Acharya and colleagues found that “most physicians support diagnostic genetic testing of high-risk children but are less supportive of expanding newborn screening, particularly for conditions

that do not meet the Wilson and Jungner criteria.” See Kruti Acharya, Paul D. Ackerman, and Lainie Friedman Ross, “Pediatricians’ Attitudes Toward Expanding Newborn Screening,” Pediatrics 116 (2005): e476-e484, p. e476.

45.  Diane B. Paul, “Patient Advocacy in Newborn Screening: Continuities and Discontinuities,” American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C (2008) 8-14.

46.  Jennifer L. Howse, Marina Weiss, and Nancy S. Green, “Critical role of the March of Dimes in the expansion of newborn screening,” Mental Retardation and Developmental Disabilities Research Reviews 12 (2006) 280-287.

47. Donald B. Bailey, Jr., Laura M. Beskow, Arlene M. Davis, and Debra Skinner, “Changing Perspectives on the Benefits of Newborn Screening,” Mental Retardation and Developmental Disabilities Research Reviews 12 (2006): 270-279, p. 275.

48.  Lainie Friedman Ross, “Screening for conditions that do not meet the Wilson and Jungner criteria: the case of Duchenne muscular dystrophy,” American Journal of Medical Genetics Part A 140A (2006): 914-922.

49.  Ibid., p. 915.

50.  If the diagnosis is made later in life, then a strong bond is allowed to form early, and the parents’ love for the child will lead them to do what is in the child’s best interest. If the diagnosis is made too early, there is a risk that a parent will see the child from the beginning as a “defective” being and not simply as “my” child. Even false-positive newborn screening results (quickly corrected) have been found to cause lasting harm to the early bonding of parent and child. See Elizabeth A. Gurian, et al., “Expanded Newborn Screening for Biochemical Disorders: The Effect of a False-Positive Result,” Pediatrics 117 (2006): 1915-1921.

51.  When a child has been identified early as genetically “abnormal,” the parents may be inclined to treat him as a second-class member of the family. Nancy Wexler tells of a woman whose two young children were at risk for Huntington’s disease and who wanted to have them tested early because “she only had enough money to send one to Harvard.” See Nancy S. Wexler, “Clairvoyance and Caution: Repercussions from the Human Genome Project,” in The Code of Codes: Scientific and Social Issues in the Human Genome Project, ed. Daniel J. Kevles and Leroy Hood (Cambridge, Massachusetts: Harvard University Press, 1992), pp. 211-243.

52.  Nancy S. Wexler, “The Tiresias complex: Huntington’s disease as a paradigm of testing for late-onset disorders,” FASEB (Federation of American Societies for Experimental Biology) Journal 6 (1992): 2820-2825. See also Wexler’s presentation before this Council on September 8, 2006, available online at www.bioethics.gov/transcripts/sept06/session6.html.

53.  Wexler, “The Tiresias complex,” p. 2824.

54.  Ibid., p. 2820, quoting Sophocles, Oedipus Tyrannos, lines 316-317. |        |