Multiple testing in the context of haplotype analysis revisited: application to case-control data.

We have lately presented a testing procedure for family data which accounts for the multiple testing problem that is induced by the enormous number of different marker combinations that can be analyzed in a set of tightly linked markers. Most methods of haplotype based association analysis already require simulations to obtain an uncorrected P value for a specific marker combination. As shown before, it is nevertheless not necessary to carry out nested simulations to obtain a global P value that properly corrects for the multiple testing of different marker combinations without neglecting the dependency of the tests. We have now implemented this approach for case-control data in our program FAMHAP, as this data structure currently plays a dominant role in the field. We consider different ways to deal with phase ambiguities and two different statistical tests for the underlying single marker combinations to obtain uncorrected P values. One test statistic is chi-square based, the other is a haplotype trend regression. The performance of these different tests in the multiple testing situation is investigated in a large simulation study. We obtain a considerable gain in power with our global P values as opposed to Bonferroni corrected P values for all suggested test statistics. Good power was obtained both with the haplotype trend regression approach as well as with the simpler chi-square based test. Furthermore, we conclude that the better strategy to deal with phase ambiguities is to assign to each individual its list of weighted haplotype explanations, rather than to assign to each individual its most likely haplotype explanation. Finally, we demonstrate the usefulness of our approach by a real data example.

Tracheal-innominate artery fistula caused by the endotracheal tube tip: case report and investigation of a fatal complication of prolonged intubation.

CASE REPORT: A patient with extensive burns was intubated with an 8.0 mm internal diameter endotracheal tube (ETT) equipped with a subglottic suction port (Mallinckrodt HiLo Evac). The ETT was secured to a left upper molar with wire sutures throughout the hospitalization course to ensure airway stability. On the 40th day of intubation, the patient exsanguinated and died from a tracheo-innominate artery fistula. Postmortem examination revealed a 1 cm lesion of the left anterior tracheal wall at the position of the ETT tip. The prolonged stationary position of the ETT was considered the primary factor responsible for the fistula. Yet tracheo-innominate artery fistula normally is associated with high cuff pressures rather than with the tube tip. The special ETT construction required for the subglottic suction feature was suspected to have increased tube rigidity and may have played a contributory role. METHODS: The rigidity of the Mallinckrodt HiLo Evac was measured with a mechanical model and compared to 5 other commercially-available ETTs. Rigidity was expressed as the force generated by the ETT tip when the tube curvature was altered by 5 cm and 10 cm of flexion from its resting position. RESULTS: The mean force exerted by the Mallinckrodt HiLo Evac was 10.1 +/- 2.8 g at 5 cm of flexion and 17.7 +/- 5.1 g at 10 cm of flexion. This was significantly greater than all other ETT brands tested (by one-way analysis of variance and Student-Newman-Kuels test, p < 0.05). CONCLUSION: This case of fatal tracheo-innominate artery fistula formation associated with an ETT tip was unusual because of the extended duration of endotracheal intubation and the complexity of the patient's airway management problems. Our data suggest that the higher rigidity of the HiLo Evac ETT may have contributed to fistula development at the tube tip. However, we do not believe that the higher rigidity of the HiLo Evac ETT necessarily poses any greater risk than other ETTs under normal circumstances, in which the tube tip is not fixed in a stationary position for an extended period.