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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           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  | *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.*
A Brief History of Newborn Screening in the United States Staff Discussion PaperBy Sam Crowe, Ph.D. 
***Abstract:**This background paper provides an overview of the practice of newborn screening in the United States. It describes the main clinical, technological, and policy developments that have shaped newborn screening since its inception. It also highlights the changes that have influenced—and continue to shape—the moral focus of the newborn screening system.*
I. The Early Years
Screening newborns for rare genetic diseases is a relatively new practice, initiated approximately forty years ago. Prior to the advent of screening, biomedical researchers and health professionals were preoccupied with the most prominent causes of newborn mortality, such as diarrheal diseases, influenza, and other infectious diseases. By 1960, however, the infant mortality rate had dropped to less than three percent of live births from over ten percent fifty years earlier. The declining rate was due, in part, to the widespread use of antibiotics; the development of vaccines, particularly the Salk and Sabin polio vaccines; improved nutrition; better education; and generally improved sanitary practices. As infant mortality rates dropped, attention shifted to the etiology of rare diseases. The first major milestone in this shift in focus occurred in 1962, when President Kennedy announced that the federal government would begin exploring the problem of mental disability—until then, a largely ignored issue. He created the President’s Panel on Mental Retardation to lead this exploration.**1**

During roughly the same time period, a major scientific breakthrough in the study of phenylketonuria, or PKU, was underway. In 1934, Dr. Asbjorn Folling of Norway first described the condition when he observed that some of his mentally disabled patients had phenylpyruvic acid in their urine, a finding indicative of a deficiency in the enzyme that converts phenylalanine to tyrosine, a necessary component for protein synthesis. When this transformation does not occur, phenylalanine accumulates in the blood. High levels of phenylalanine are toxic to the developing brain of an infant and cause mental retardation. At the time, the preventive strategy was to reduce phenylalanine levels in the patient’s diet. This approach had one serious drawback, though. Phenylalanine is an essential amino acid necessary for proper growth, so deficiencies in it may also lead to mental retardation. 

Despite this risk, the younger siblings of children with PKU were given diets low in phenylalanine from a very early age. The results were somewhat encouraging and, in light of the evidence of benefit from this special diet, two therapeutically promising research initiatives were launched. One was to devise a source of protein free of phenylalanine. The outcome was the infant formula Lofenalac, which is still in use today. The other initiative was aimed at developing a method for detecting high phenylalanine levels before damage to the developing brain could occur.

Dr. Robert Guthrie led the second initiative, which yielded a breakthrough in the early 1960s. He developed a test to detect PKU before it is clinically symptomatic. The test consisted of a culture of Bacillus subtilis and B-2-thienylalanine, which inhibits the growth of the bacteria. Once a blood sample from the newborn was added to this culture, the bacteria would leach the phenylalanine from the blood spot, overcome the inhibition caused by the B-2-thienylalanine, and grow. Bacterial growth beyond a normal range indicated elevated levels of phenylalanine and thus the presence of PKU in the newborn.**2**

The test was not perfect. Over the next few years, it produced quite a few false positives, and some children unnecessarily received low phenylalanine diets. To compound the problem, there was uncertainty about the amount of phenylalanine to cut from the diet; as a result, some healthy children developed mental disabilities because of the treatment.**3** Nevertheless, PKU screening was generally considered a success, and spurred questions about whether other diseases might be prevented through early detection as well. After further study it became clear that they could. By the late 1960s, newborn screening for rare genetic diseases had become a permanent part of infant health care in the United States. 

 As newborn screening grew, a few national and international groups took notice and began to explore the moral implications of the practice. The most influential report, though, was not actually about newborn screening: it concerned screening for “chronic diseases of adults in developed countries.”**4** Published in 1968 by the World Health Organization and entitled Principles and Practice of Screening for Disease, this report recommends ten principles to guide the screening for chronic disease—now commonly known as the Wilson-Jungner principles. Because of their relevance and their moral validity, these principles were soon applied to newborn screening programs throughout the United States, where they served as guidelines for many years. These 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 stage.                5. There should be a suitable test or examination.                6. The test 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.**5**

 Half of these principles describe what makes a condition acceptable for screening. The first principle states that the condition should be an important health problem. According to the report, two kinds of conditions meet this requirement: those that are extremely harmful to the health of the person affected and those that have a high incidence in the population. The second principle states that the condition should be treatable. The report makes the following statement about this principle: “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** The fourth principle states that the condition’s early symptomatic or latent stage should be recognizable. Otherwise the main goals of screening—to detect a condition and to treat it early—would not be attainable. The fifth principle states that there should be an effective test for a condition before it is included in a screening panel. According to the authors, the screening tests can have a higher margin of error and be less valid than diagnostic tests, but they should have a very low false negative rate. The seventh principle states that the natural history of a condition should be understood for it to be included, once again because the goal of screening is to detect a condition and then treat it before it causes irreversible harm. 

The other principles aim to ensure the usefulness and continued success of screening programs. The third principle states that there should be facilities for diagnosis and treatment when a condition is detected through screening. The sixth principle states that the screening test should be acceptable to the public. If it is not, its use will not be supported. The eighth principle states that there should be a policy that clarifies who should be considered a patient, and thus receive treatment. For those who clearly have a disease, treatment should be offered. For the borderline cases that fall between diseased and normal, however, the person’s personal physician should follow up to monitor that person’s status. The ninth principle states that the cost of screening should be reasonable and acceptable, while the tenth principle states that once begun, screening programs should always be available in order for every generation to benefit.**7**

The moral focus of these principles is, first and foremost, the               welfare of the adult who is screened. When these principles are               applied to newborn screening, the moral focus is the child, particularly               that child's medical needs and benefits. This focus has been repeatedly               affirmed since the Wilson-Jungner principles were first applied               to newborn screening.**8**
II. Newborn Screening Today
Even with such affirmation, the moral focus of newborn screening programs has changed recently. This change has been made easier by the following developments. First, newborn screening for rare genetic diseases has become much more organized, and now consists of a complete “system,” of which screening is one part. Second, it has benefited from major advances in technology that make it possible to screen for many conditions using only one test. Third, it has expanded to such an extent that all but one state will soon screen for at least thirty conditions, while thirty of these states will soon screen for over fifty conditions. Each of these changes is described in more detail in the following sections.

**A. The Screening System**

During the early days of newborn screening, there was not a defined, organized screening system per se. As newborn screening expanded, distinct components of the process developed, and by the early 1990s, the Council of Regional Networks for Genetic Services, a major professional organization in the field, described several of these components. In 2000, the organization revisited the issue and identified the five most significant components: screening, follow-up, diagnosis, management, and evaluation. 

The first step, screening, begins with the collection of a blood sample (from the heel and on filter paper), usually between twenty-four and ninety-six hours after birth and typically before discharge from the hospital. Laboratory analysis measures the concentration of specific chemical compounds in the sample in comparison with a defined range of normal values. Follow-up testing is necessary: even with advances in screening technology, false positive rates remain high.**9**Confirmed abnormal test results are reported to the newborn’s primary care physician or pediatrician, who communicates them to the parents. Further evaluation is often needed to ensure proper diagnosis. Newborns identified with a genetic disease are referred to metabolic specialists who develop a specific treatment plan for the care and treatment of the child. Disease management will continue throughout the affected child’s life. Moreover, to ensure that the newborn screening system as a whole is working effectively, continuous assessment is necessary.**10**

**B. Today’s Technology**

Within the last five years, most screening programs in the United States have begun to use tandem mass spectrometry (MS/MS) as the principal tool for analyzing blood spots. MS/MS has reduced false positive results—although they still remain a problem—and it has made the screening process easier: the test can screen for over forty metabolic conditions.**11**Before MS/MS was used for newborn screening, a separate bacterial assay was needed for each condition. Now only endocrine disorders (i.e., congenital hypothyroidism and congenital adrenal hyperplasia), hemoglobin disorders (i.e., sickle cell disease, S-beta thalassemia, and sickle-C disease), and a few others (e.g., biotinidase, cystic fibrosis, transferase deficient galactosemia, and hearing disorders) need separate tests. 

 A mass spectrometer is an analytical instrument that weighs molecules. It can determine exactly what kinds of molecules are in a specific sample and the quantity of each kind of molecule present. In MS/MS, two mass spectrometers are connected together by a chamber called a collision cell. The collision cell’s job is to disaggregate the molecules after one of the mass spectrometers has weighed and sorted them. The other mass spectrometer then sorts and weighs the pieces of the molecules that are of interest to those conducting the screening, typically amino acids and acylcarnitines.**12**

Measurements of amino acids and acylcarnitines are critical in detecting disease. High levels of them indicate that the child has a potentially dangerous metabolic disorder. In such cases, there is impaired function of the enzymes responsible for the breakdown of amino acids or the conversion of fat into energy. As a result, the compounds accumulate in the blood to toxic levels. Tandem mass spectrometry is the most reliable, widely available method for measuring these compounds in a child’s blood.**13**

**C. Current Policy**

Both federal and state governments make policy governing newborn               screening. The federal government plays a comparatively limited               role in the process. It offers grants to help states pay for screening               costs and research.**14**               It has working committees designed to explore the ethical, social,               clinical, and political implications of newborn screening.**15**               It ensures that laboratories processing the screening tests meet               strict standards.**16**               And it approves the screening tests themselves for public use.**17**

The state governments, on the other hand, play a much larger role               in shaping screening programs. Each state chooses the screening               tests to be used within its jurisdiction. Each state chooses the               panel of conditions the screening will cover. Each state is responsible               for ensuring that every newborn within its borders at least has               the opportunity to be screened. Finally, each state pays for most               of the costs of the screening process.**18**

Although the states have virtually unlimited freedom to determine how to organize and conduct their own screening programs, many states have at least a few similar policies. For example, many states have privacy and confidentiality policies to protect personal information, including genetic information. Many states allow the parents to opt out of the screening. And many states have education programs that provide parents with information on the screening process, such as the conditions being screened for, a description of the conditions, the manner of the collection procedure, and an explanation of why the health care professionals might need to retest.**19**

Just as there are important similarities between the programs,               there are also significant differences. One of the main differences               is in the quality of parental education. Many states do not provide               parents with information on the accuracy of screening, the possibility               of false positives, when the results of the screening tests will               be available, the privacy and confidentiality laws governing the               information obtained, or how the parents might decline the offer               for screening. Another difference between the states is in the cost               of screening. Some states charge less than fifteen dollars while               other states charge over seventy. Still another difference is in               the number of initial screening tests required, with some states               requiring only one and other states requiring two.**20**

Perhaps of greatest importance is the increasing size of the panel of conditions of most states. All but one state currently or will soon screen for at least thirty conditions. Thirty of those states currently or will soon screen for over fifty conditions, with Illinois, Mississippi, and Pennsylvania offering screening for fifty-seven conditions. The one exception is Washington, which screens for only fifteen conditions.**21**Less than one year ago, Washington’s panel was considered relatively large, however. External pressure generated by a groundbreaking report calling for panel expansion,**22** which is discussed in the next section, and the internal pressure to keep up with other states**23**have led to this rapid increase in panel size across the states.

**D. The Moral Focus of Today’s Screening Programs**

As mentioned, when applied to newborn screening, the Wilson-Jungner               principles make the medical needs and benefits of the screened newborn               the foci of the activity. These principles guided the newborn screening               programs in the United States until fairly recently when the moral               focus of the screening system began to change, in large part because               of a report published in 2005 by the American College of Medical               Genetics (ACMG). The Maternal and Child Health Bureau (MCHB) of               the Health Resources and Services Administration commissioned the               ACMG to write a report assessing the strengths and weaknesses of               state newborn screening programs. At the time, there was considerable               variation in screening panels from state to state, with some states               screening for as few as eight conditions while other states were               screening for over forty. This variation caused an outcry among               some screening experts and the public. They were concerned that               the early detection of a deadly genetic disease or lack thereof               depended on where in the United States a child was born.**24**               In response to this perceived injustice, the MCHB asked the ACMG               to make recommendations on the following subjects: a uniform condition               panel, model policies for state screening programs, model minimum               standards for state programs, a model decision matrix for consideration               of state program expansion, and consideration of the use of national               quality assurance and oversight.**25**

The ACMG evaluated eighty-four conditions during its study. It divided the conditions into three categories based on its assessment: the “core panel;” “secondary targets,” which consists of conditions that are parts of the differential diagnosis of core panel conditions; and “not appropriate for newborn screening,” which includes conditions that do not have a screening test or that received poor criteria evaluations. The evaluations were designed to determine the extent to which scientific and clinical evidence supports the availability of a test and treatment, whether the understanding of the history of the condition is sufficient, and whether the information obtained through screening would indicate the presence of the condition or of a carrier state. The ACMG report proposes that every state mandate screening for twenty-nine core conditions and report on twenty-five other conditions that are a part of the differential diagnosis of a condition in the core panel.**26** Supporters of this proposal claim that fewer sick children would be left undetected if the states adopted this uniform panel of tests. As of the beginning of 2008, all but one state screens for or plans to screen for in the near future over thirty of the conditions recommended by the ACMG. The ACMG’s goal has not yet been met, but considerable progress has been made. 

The push to create a uniform panel for every state, however, is not what has changed the moral focus of newborn screening in the United States. In addition to this push, the ACMG report also explicitly broadens the moral focus of screening to include both the medical needs and benefits of the newborn being screened and the benefits and interests of the newborn’s family and society.**27**The genetic information collected is of particular use to the family, or more specifically the parents, not only because it potentially translates into therapies for their child but also because of its practical value to the parents themselves. For example, the parents of an ill child might make different lifestyle decisions than they would if the child were not ill. They might choose to live in a different part of town in order to be closer to a specific school or medical facilities. If they knew that there was a high probability that any additional offspring would have a debilitating genetic disease, they might choose not to have any more children, or they might choose to use prenatal genetic diagnosis in subsequent pregnancies. Unlike the benefits and interests of specific families, the benefits and interests of society are more general in kind, and include the advancement of science: society benefits most from the acquisition of new genetic information that leads to new knowledge concerning the incidence and the natural history of genetic diseases. 

The import of this broader moral focus can be seen in the ACMG’s abandonment of the Wilson-Jungner principle of screening for treatable conditions only. While the ACMG claims that all of the twenty-nine conditions in the core panel have “available and efficacious treatments,”**28**twelve of the twenty-nine disorders have an incidence of less than one per one hundred thousand live births. It is difficult to know how effective some of these treatments are because the rarity of these diseases impedes well-designed controlled studies that are necessary to make such a determination.**29** Even if the efficacy of the treatment for each of the core conditions was indisputable, the ACMG does not even imply that the recommended secondary targets for its uniform screening panel are treatable. In fact, the report states that the secondary target panel consists of “a group of conditions that are part of the differential diagnosis of higher scoring conditions, but for which natural history is less well understood or efficacious treatment is lacking.”**30**As the states continue to expand their screening programs to include even more of these secondary target conditions, a new kind of newborn screening is slowly becoming a reality: the old dogma of Wilson-Jungner is giving way to a new dogma, one that promotes screening for as yet untreatable diseases.

With the inclusion of the benefits and interests of society in the moral focus of today’s newborn screening programs, screening for untreatable diseases will become the norm. But screening newborns for untreatable diseases is only one new practice possible under such a broad moral focus. Newborn predictive genetic screening, or screening for genetic susceptibility to disease, also would be acceptable, primarily because of societal interest: once children who have an increased risk for late-onset diseases are identified, they can be monitored to help researchers learn more about any latent stages of the diseases. 

A few pilot studies exploring this kind of screening began even before the ACMG report was issued. During the late 1990s, a screening program called Prospective Assessment in Newborns for Diabetes Autoimmunity (PANDA) was created in Florida. Under PANDA, newborns are screened for the genetic markers of susceptibility to type 1 diabetes, an unpreventable disease that usually becomes manifest in puberty.**31** In 2002, a similarly functioning program called The Environmental Determinants of Diabetes in the Young, or TEDDY, began. A few hospitals in Colorado, Florida, Georgia, New York, Pennsylvania, and Washington currently participate in TEDDY.**32**Screening for type 1 diabetes is only the tip of the proverbial iceberg. By 2005, some experts were already claiming that predictive genetic testing was available for one thousand diseases.**33** As newborn screening continues to expand in scope, such conditions one day might be included in mainstream programs. 
III. A New Look for Newborn Screening
In the last forty years, newborn screening in the United States has undergone a slow but steady expansion. The interests of the family and of society at large are now considered critical to its ethical justification—not just the medical needs and benefits of the screened newborn. With the broadening of its moral focus, newborn screening is now used to detect untreatable diseases and uncover genetic susceptibility for late-onset genetic diseases. By including these conditions in screening programs, geneticists hope eventually to develop efficacious treatments for some of the worst genetic diseases, but for most diseases, such treatments will take many years to develop. The immediate consequence of the broadening of moral focus and of the inclusion of untreatable and late-onset diseases in screening panels is clear: whereas screening programs were once tools for identifying and treating rare genetic diseases, they are increasingly tools for expanding our genetic knowledge. As newborn screening continues to grow in scope, this emergent emphasis on research promises only to intensify.

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FOOTNOTES
1. Brosco, Jeffrey, et al., “Early History of Universal Screening for PKU and Galactosemia in the US,” Mailman Center for Child Development, Department of Pediatrics, University of Miami, Quarterly Narrative Report, January-March 2006.

2.  Guthrie, Robert and Susi, Ada, “A Simple Phenylalanine Method for Detecting Phenylketonuria in Large Populations of Newborn Infants,” Pediatrics, 1963, Vol. 32, pp. 338-343.

3. Brosco, Jeffrey, et al., “Early History of Universal Screening for PKU and Galactosemia in the US,” Mailman Center for Child Development, Department of Pediatrics, University of Miami, Quarterly Narrative Report, January-March 2006.

4. Wilson, J.M.G., and G. Jungner, Principles and Practice of Screening for Disease, 1968, p. 8.

5. Ibid., pp. 26-27.

6. Ibid., p. 27.

7. Ibid., pp. 27-38.

8. See, for instance, the IOM’s 1994 report Assessing Genetic Risks: Implications for Health and Social Policy; the 1995 ASHG/ACMG report “Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents;” the 1997 NIH report Promoting Safe and Effective Genetic Testing in the United States; and the 2000 American Academy of Pediatrics report “Serving the Family from Birth to the Medical Home: Newborn Screening: A Blueprint for the Future.” The main counterexample is the 1975 National Research Council’s report Genetic Screening Programs: Principles and Research. Like the approach in vogue today, it promotes a broader conception of benefit, which includes that of the family and of society. 

9. Gurian, Elizabeth, et al., “Expanded Newborn Screening for Biochemical Disorders: The Effect of a False-Positive Result,” Pediatrics, 2006, Vol. 117, No. 6, pp. 1915-1921; Tarini, Beth, et al., “State Newborn Screening in the Tandem Mass Spectrum Era: More Tests, More False-Positive Results,” Pediatrics, 2006, Vol. 118, pp. 448-456; Waisbren, Susan, “Newborn Screening for Metabolic Disorders,” JAMA, 2006, Vol. 296, No. 8, pp. 993-995. 

10. Botkin, Jeffrey, et al., “Newborn Screening Technology: Proceed With Caution,” Pediatrics, 2006, Vol. 117, No. 5, pp. 1793-1799.

11.The metabolic               category consists of three subcategories: fatty acid disorders,               organic acid disorders, and amino acid disorders. There are five               or more conditions within each of these subcategories. Fatty acid               disorders are disorders that are caused by the failure of enzymes               that help convert fat into energy. Fat must be used to assist with               the production of energy when the body runs out of glucose, the               principal source for energy production. When the body does not have               any glucose to convert and cannot convert fat, the cells of the               body suffer an energy crisis, which can sometimes lead to coma or               to death. Two examples of fatty acid disorders are medium-chain               acyl-CoA dehydrogenase deficiency and very long-chain acyl-CoA dehydrogenase               deficiency. 

Organic acid metabolism disorders are inherited               disorders caused by the failure of an enzyme that usually breaks               down amino acids, lipids, or sugars. When these substances are not               broken down, toxic acids accumulate in the body. If not properly               treated, these disorders can lead to coma or death during the first               month of the newborn’s life. Two examples of organic acid               metabolism disorders are isovaleric academia and glutaric academia               type 1. 

Amino acid disorders are caused by one of two events.               Either the enzymes that help breakdown amino acids fail to perform               their task, or the enzymes that assist the body in expelling the               nitrogen incorporated in amino acid molecules do not expel it. Then               toxic levels of either amino acids or ammonia build up in the body               and cause illnesses of varying degrees. Two examples of amino acid               disorders are phenylketonuria and maple syrup urine disease. 

See Newborn Screening: Toward a Uniform Screening Panel and System, the National Newborn Screening and Genetics Resource Center’s “National Newborn Screening Status Report,” and the March of Dimes website for more information on these conditions. 

12.Recent studies have shown that MS/MS also can be used to detect lysosomal storage disorders, such as Fabry, Gaucher, Krabbe, Niemann-Pick, and Pompe, but the assays for these disorders have yet to be included in most MS/MS platforms. New York is one exception. Children born there are screened for Krabbe disease. See for more information: Gelb, Michael, et al., “Direct Multiplex Assay of Enzymes in Dried Blood Spots by Tandem Mass Spectrometry for the Newborn Screening of Lysosomal Storage Disorders,” Journal of Inheritable Metabolic Disease, 2006, Vol. 29, pp. 397-404; Li, Yijun, et al., “Direct Multiplex Assay of Lysosomal Enzymes in Dried Blood Spots for Newborn Screening,” Clinical Chemistry, 2004, Vol. 50, No. 10, pp. 1785-1796; and Millington, David, “Newborn Screening for Lysosomal Storage Disorders,” Clinical Chemistry, 2005, Vol. 51, No. 5, pp. 808-809. 

13. ACMG/ASHG, “Tandem Mass Spectrometry in Newborn Screening,” Genetics in Medicine, 2000, Vol. 2, No. 4, pp. 267-269; Banta-Wright, Sandra, and Robert Steiner, “Tandem Mass Spectrometry in Newborn Screening, A Primer of Neonatal and Perinatal Nurses,” Journal of Perinatal and Neonatal Nursing, 2004, Vol. 18, No. 1, pg. 41-58; and Chace, Donald, “A Layperson’s Guide to Tandem Mass Spectrometry and Newborn Screening,” www.savebabies.org. 

14. Section               300b-8 of Title 42 of the United States Code states that the Secretary               must award grants to entities to improve state and local health               agencies’ ability to provide screening, counseling, or health               care services to newborns and children who have or are at risk for               heritable disorders. Also see Sections 300b-1, 300b-6, and 300b-9               for more details on the federal government’s role.

15. Section               300b-10 of Title 42 states that the Secretary must establish the               “Advisory Committee on Heritable Disorders in Newborns and               Children.” The committee will offer advice to the Secretary               on grants awarded under Sec. 300b-8.

16.  The Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), which improved upon the Clinical Laboratory Improvement Act of 1967 (CLIA-67), is the law that permits the Secretary of HHS to create quality standards for laboratory testing. Laboratories can choose to receive CLIA certification either by an appropriate state agency or by an approved private organization, such as the Joint Commission on Accreditation of Healthcare Organizations, the College of American Pathologists, or the American Society for Histocompatibility and Immunogenetics. HHS, through the Centers for Medicare and Medicaid (CMS), published most of the regulations pertaining to CLIA in 1992. 

At the time CLIA-88 was enacted and its regulations made, tandem mass spectrometry was just becoming available and the Human Genome Project was just beginning. Much in genetics and genetic testing has changed since then. So while genetic testing labs are subject to CLIA-88, some have argued that the law offers very little guidance regarding genetic testing. Even back in 1997, the National Institutes of Health-Department of Energy Task Force on Genetic Testing issued a report calling for the HHS Clinical Laboratory Improvement Advisory Committee (CLIAC) to recommend the creation of a subspecialty on genetics in order to address this shortcoming of CLIA-88. CLIAC then proposed some changes to the regulation in 1998. In 2000, the Secretary’s Advisory Committee on Genetic Testing (SACGT), the predecessor to the Secretary’s Advisory Committee of Genetics, Health, and Society (SACGHS), also acknowledged this shortcoming of the law and supported CLIAC’s recommendations. In 2003, HHS revised the CLIA regulations and included some of CLIAC’s proposals. Nevertheless, some continued to maintain that a separate subspecialty for genetic screening should be created. But in November 2006, CMS told SACGHS that there is no need for a subspecialty for genetic testing, and that in fact CLIA-88 regulations already fully cover genetic testing. For more information see the CMS website, www.cms.hhs.gov.

In addition to the role of CMS, the Center for Disease Control and Prevention’s Environmental Health Laboratory evaluates the performance of laboratories involved in the analysis of newborn screening tests and provides technical assistance to resolve diagnostic problems. For more information see the CDC website, www.cdc.gov.

17. The FDA is responsible for ensuring the safety and efficacy of medical devises. Included within this category are genetic tests and newborn screening tests more specifically. Recently, the FDA has been considering tandem mass spectrometry. In fact, in 2004 the Center for Devices and Radiological Health of the FDA produced a document detailing the guidance for industry and FDA staff on tandem mass spectrometry. As technology advances, the FDA will be required to consider the safety and efficacy of new developments, such as DNA chip tests. For more information see the FDA website, www.fda.gov. 

18. Johnson, Kay, et al., “Financing State Newborn Screening Programs: Sources and Uses of Funds,” Pediatrics, 2006, Vol. 117, No. 5, pp. s270-s279; Therrell, Bradford, et al., “Status of Newborn Screening Programs in the United States” in Pediatrics, 2006, Vol. 117, No. 5, pp. s212-s252.

19. Therrell, Bradford, et al., “Status of Newborn Screening Programs in the United States” in Pediatrics, 2006, Vol. 117, No. 5, pp. s212-s252.

20. Ibid.

21. National Newborn Screening and Genetics Resource Center, “National Newborn Screening Status Report,” January 3, 2008.

22. American College of Medical Genetics, Newborn Screening: Toward a Uniform Screening Panel and System, 2005.

23. Texas State Representative Myra Crownover said “babies in Texas are at a huge disadvantage simply because they are born in our state…” Texas House of Representatives Press Release, April 14, 2005.

24.  Alexander, Duane, and Peter C. van Dyck, “A Vision of the Future of Newborn Screening,” Pediatrics, Vol. 117, No. 5, pp. s350-s354.

25. ACMG, Newborn Screening: Toward a Uniform Screening Panel and System, 2005.

26. Ibid.

27. Ibid., p. 25.

28. ACMG, Newborn Screening: Toward a Uniform Screening Panel and System, 2005, p. 62.

29. Natowicz, Marvin, “Newborn Screening—Setting Evidence-Based Policy for Protection,” New England Journal of Medicine, Vol. 353, No. 9, pp. 867-870.

30. ACMG, Newborn Screening: Toward a Uniform Screening Panel, 2005, p. 63.

31. Friedman Ross, Lainie, “Minimizing Risks: The Ethics of Predictive Diabetes Mellitus Screening Research in Newborns,” Archives of Pediatrics and Adolescent Medicine, 2003, Vol. 157, pp. 89-95; Steward, Alison, “Diabetes Genetic Susceptibility Screening Planned for Florida,” PHG Foundation website, www.phgfoundation.org, January 11, 2002.

32. See the TEDDY website, http://teddy.epi.usf.edu/, for more information.

33. Hood, Korey, et al., “Depressive Symptoms in Mothers of Infants Identified as Genetically at Risk for Type 1 Diabetes,” Diabetes Care, 2005, Vol. 28, No. 8, pp. 1898-1903. |        |