I decided its a matter of personal preference and playstyle. I use Major and Superior runes on almost all my heroes. In fact, my MM uses Superior Death, Major Soul Reaping, Minor Blood, Attunement, and Major Vigor, with 4 MM Insignias and 1 Bloodstained Insignia. My MM hero rarely dies, and if she does, the whole team is usually dead anyway.
I decided the ability to have more damage output from Superior Runes allows for things to die faster. When things die faster, I don't have to worry as much about staying alive, as there isn't much killing my team.
I have Legendary Vanquisher, and Legendary Guardian, so I do know Hard Mode, and this has worked well for me. Heroes I use with Superior runes are:
Livia (Death)
Master of Whispers (Curse)
Zhed Shadowhoof (Water)
Acolyte Sousuke (Fire)
Vekk (Air)
Koss (Strength)
Xandra (Channeling)
Razah (Spawning Power)
Melonni (Mysticism)
Khamu (Scythe Mastery)
Norgu (Illusion)
Gwen (Domination)
Heroes with Major runes:
Dunkoro (Healing Prayers+Divine Favor)
Tahlkora (Protection Prayers+Divine Favor)
Ogden Stonehealer (Smiting+Divine Favor)
Margrid The Sly (Marksmanship+Wilderness Survival)
Acolyte Jin (Expertise+Beast Mastery) - thumper

Pyre Fierceshot (Marksmanship+Expertise)
Olias (Blood)
Jora (Swordsmanship+Tactics)
Goren (Hammer Mastery+Strength)
Zenmai (Dagger Mastery+Critical Strikes)
Anton (Shadow Arts+Dagger Mastery)
General Morgahn (Spear Mastery+Leadership)
Hayda (Motivation)